Tag: Science

Hepatitis – Parkinson’s goes viral?

~ Simon ~ 11 Comments

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Last week a new piece of Parkinson’s disease research has been widely discussed in the media.

It involves Hepatitis – the viral version of it at least.

In today’s post we will review the research and discuss what it may mean for Parkinson’s disease.

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A lewy body (brown with a black arrow) inside a cell. Source: Cure Dementia

A definitive diagnosis of Parkinson’s disease can only be made at the postmortem stage with an examination of the brain. Until that moment, all cases of Parkinson’s disease are ‘suspected’.

Critical to that postmortem diagnosis is the presence of circular shaped, dense clusters of proteins, called Lewy bodies (see the image above for a good example).

What causes Lewy bodies? We don’t know, but many people have theories.

This is Friedrich Heinrich Lewy (1885-1950).

DrLewy

Friedrich Lewy. Source: Lewy Body Society

As you can probably guess, Friedrich was the first to discover the ‘Lewy body’. His finding came by examining the brains of 85 people who died with Parkinson’s disease between 1908 – 1923.

In 1931, Friedrich Lewy read a paper at the International Congress of Neurology in Bern. During that talk he noted the similarities between the circular inclusions (called ‘negri bodies’) in the brains of people who suffered from rabies and his own Lewy bodies (observed in Parkinson’s disease).

rabies

A Negri body in a cell affected by rabies (arrow). Source: Nethealthbook

Given the similarities, Lewy proposed a viral cause for Parkinson’s disease.

Now, the idea that Parkinson’s disease could have a viral component has existed for a long time – even before Lewy made his conclusion. As we have previous mentioned, theories of viral causes for Parkinson’s have been circulating ever since the 1918 flu pandemic (Click here to read our post on this topic).

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An example of post-encephalitic Parkinsonism. Source: Baillement

About the same time as the influenza virus was causing havoc around the world, another condition began to appear called ‘encephalitis lethargica‘ (also known as post-encephalitic Parkinsonism). This disease left many of the victims in a statue-like condition, both motionless and speechless – similar to Parkinson’s disease. Initially, it was assumed that the influenza virus was the causal factor, but more recent research has left us not so sure anymore.

Since then there, however, has been additional bits of evidence suggesting a viral role in Parkinson’s disease. Such as this report:

H1N1

Title: Highly pathogenic H5N1 influenza virus can enter the central nervous system and induce neuroinflammation and neurodegeneration.
Author: Jang H, Boltz D, Sturm-Ramirez K, Shepherd KR, Jiao Y, Webster R, Smeyne RJ.
Journal: Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):14063-8.
PMID: 19667183

The researchers in this study found that when they injected the highly infectious H5N1 influenza virus into mice, the virus progressed from the periphery (outside the brain) into the brain itself, where it induced Parkinson’s disease-like symptoms. The virus also caused a significant increase in the accumulation of the Parkinson’s associated protein Alpha Synuclein. Importantly, they witnessed the loss of dopamine neurons in the midbrain of the mice 60 days after resolution of the infection – that cell loss resembling what is observed in the brains of people with Parkinson’s disease.

The Parkinson’s associated protein alpha synuclein has also recently demonstrated anti-viral properties:

Beckham

Title: Alpha-Synuclein Expression Restricts RNA Viral Infections in the Brain.
Authors: Beatman EL, Massey A, Shives KD, Burrack KS, Chamanian M, Morrison TE, Beckham JD.
Journal: J Virol. 2015 Dec 30;90(6):2767-82. doi: 10.1128/JVI.02949-15.
PMID: 26719256               (This article is OPEN ACCESS if you would like to read it)

David Beckham (not the football player) and his research colleagues introduced West nile virus to brain cells grown in cell culture and they observed an increase in alpha synuclein production. They also found that the brains of people with West nile infections had increased levels of alpha synuclein.

The researchers then injected West Nile virus into both normal mice and genetically engineered mice (which produced no alpha synuclein) and they found that the genetically engineered mice which produced no alpha synuclein died quicker than the normal mice. They reported that there was an almost 10x increase in viral production in the genetically engineered mice. This suggested to them that alpha synuclein may be playing a role in protecting cells from viral infections.

Interesting, but what about this new data involving Hepatitis?

Yes, indeed. Let’s move on.

Wait a minute, what is Hepatitis exactly?

The name Hepatitis comes from the Greek: Hepat – liver; and itis – inflammation, burning sensation. Thus – as the label suggests – Hepatitis is inflammation of liver tissue.

Progress-of-Liver-Damage

Hepatitis and the liver. Source: HealthandLovepage

It can be caused by infectious agents (such as viruses, bacteria, and parasites), metabolic changes (induced by drugs and alcohol), or autoimmune/genetic causes (involving a genetic predisposition).

The most common cause of hepatitis is viral.

There are five main types of viral hepatitis (labelled A, B, C, D, and E). Hepatitis A and E are mainly spread by contaminated food and water. Both hepatitis B and hepatitis C are commonly spread through infected blood (though Hepatitis B is mainly sexually transmitted). Curiously, Hepatitis D can only infect people already infected with hepatitis B.

Hepatitis A, B, and D are preventable via the use of immunisation. A vaccine for hepatitis E has been developed and is licensed in China, but is not yet available elsewhere

Hepatitis C, however, is different.

There is currently no vaccine for it, mainly because the virus is highly variable between strains and the virus mutates very quickly, making an effective vaccine a difficult task. A number of vaccines under development (Click here for more on this).

What is known about Hepatitis C and the brain?

Quite a bit.

Similar to HIV (which we discussed in a previous post), the hepatitis C virus (HCV) enters the brain via infected blood-derived macrophage cells. In the brain, it is hosted by microglial cells, which results in altered functioning of those microglial cells. This causes problems for neuronal cells – including dopamine neurons. For example, people infected with HCV have reduced dopamine transmission, based on brain imaging studies (Click here and here for more on this result).

Have there been connections between hepatitis C virus and Parkinson’s disease before?

Yes.

Dopatitle

 

Title: Hepatitis C virus infection: a risk factor for Parkinson’s disease.
Authors: Wu WY, Kang KH, Chen SL, Chiu SY, Yen AM, Fann JC, Su CW, Liu HC, Lee CZ, Fu WM, Chen HH, Liou HH.
Journal: J Viral Hepat. 2015 Oct;22(10):784-91.
PMID: 25608223

The researchers in this study used data collected from a community-based screening program in north Taiwan which involved 62,276 people. The World Health Organisation (WHO) estimates that the prevalence of hepatitis C viral infection worldwide is approximately 2.2–3%, representing 130–170 million people. Taiwan is a high risk area for hepatitis, with antibodies for hepatitis viruses in Taiwan present in 4.4% in the general population (Source).

The researchers found that the significant association between hepatitis C viral infections and Parkinson’s disease – that is to say, a previous infection of hepatitis C increased the risk of developing Parkinson’s disease (by 40%). The researchers then looked at what the hepatitis C and B viral infections do to dopamine neurons growing in cell culture. They found that hepatitis C virus induced 60% dopaminergic cell death, while hepatitis B had no effect.

This study was followed up a few months later, by a second study suggesting an association between Hepatitis C virus and Parkinson’s disease:

Hep title

Title: Hepatitis C virus infection as a risk factor for Parkinson disease: A nationwide cohort study.
Authors: Tsai HH, Liou HH, Muo CH, Lee CZ, Yen RF, Kao CH.
Journal: Neurology. 2016 Mar 1;86(9):840-6.
PMID: 26701382

The researchers in this study wanted to investigate whether hepatitis C could be a risk factor for Parkinson’s disease. They did this by analyzing data from 2000-2010 drawn again from the Taiwan National Health Insurance Research Database.

The database included 49,967 people with either hepatitis B, hepatitis C or both, in addition to 199,868 people without hepatitis. During the 12 year period, 270 participants who had a history of hepatitis developed Parkinson’s disease (120 still had hepatitis C). This compared with 1,060 participants who were free of hepatitis, but went on to develop Parkinson’s disease.

When the researchers controlled for potentially confounding factors (such as age, sex, etc), the researchers found participants with hepatitis C had a 30% greater risk of developing Parkinson’s disease than the controls.

So if this has been demonstrated, why is this new study last week so important?

Good question.

The answer is very simple: This study is not based on statistics from Taiwan – this new study has found the same result from a new population.

HEP TITLE

Title: Viral hepatitis and Parkinson disease: A national record-linkage study.
Authors: Pakpoor J, Noyce A, Goldacre R, Selkihova M, Mullin S, Schrag A, Lees A, Goldacre M.
Journal: Neurology. 2017 Mar 29. [Epub ahead of print]
PMID: 28356465

These researchers used the English National Hospital Episode Statistics database and linked it to mortality data collected from 1999 till 2011. They too have found a strong association between hepatitis C and Parkinson’s disease (standardized rate ratio 1.51, 95% CI 1.18–1.9).

Curiously (and different from the previous studies), the researchers in this study also found a strong association for hepatitis B and Parkinson’s disease (standardized rate ratio 1.76, 95% CI 1.28–2.37). And these associations appear to be specific to Hepatitis B and C, as the investigators did not find any association between autoimmune hepatitis, chronic hepatitis, or HIV.

One important caveat with this new study, however, is that the authors could not
control for lifestyle factors (such as smoking or alcohol consumption). In addition, their system of linking medical records may underestimate the numbers of patients with
Parkinson’s disease as it would not take into account people with Parkinson’s disease who do not seek medical advice or those who are misdiagnosed (given a wrong diagnosis – it does happen!).

Regardless of these cautionary notes, the results still add to the accumulating evidence of an association between the virus that causes Hepatitis and the neurodegenerative condition of Parkinson’s disease.

But what about those people with Parkinson’s disease who have never had Hepatitis?

Yeah, this is a good question.

But there is a rather uncomfortable answer to it.

Here’s the rub: “Approximately 70%–80% of people with acute Hepatitis C do not have any symptoms” (Source: Centre for Disease Control). That is to say, the majority of people infected with the Hepatitis C virus will not be aware that they are infected. Some of those people who are infected may think that they have a case of the flu (HCV symptoms include fever, fatigue, loss of appetite,…), while others will simply not display any symptoms at all.

So many people with Parkinson’s disease may have had HCV, but never been aware of it.

And this is the really difficult part of researching the causal elements of Parkinson’s disease.

The responsible agent may actually leave little or no sign that they were ever present. For a long time, people have suggested that Parkinson’s disease is caused by a thief in the night – some agent that comes in, causes a problem and disappears without detection.

Perhaps Hepatitis is that thief.

But hang on a second, 60–70% of HCV infected people will go on to develop chronic liver disease (Source). Do people with Parkinson’s disease have liver issue?

Umm, well actually, in some cases: yes.

There have been studies of liver function in Parkinson’s disease where abnormalities have been found (Click here for more on this). And dopamine cell dysfunction has been seen in people with cirrhosis issues (Click here for more on this). In fact, the prevalence of Parkinsonism in people with cirrhosis has been estimated to be as high as 20% (and Click here for more on that).

So what are we saying? Hepatitis causes Parkinson’s disease???

No, we are not saying that.

Proving causality is the hardest task in science.

In addition, there have been a few studies in the past that have looked at viral infections as the cause of Parkinson’s disease that found strong associations with other viruses. For example this study:

Title: Infections as a risk factor for Parkinson’s disease: a case-control study.
Authors: Vlajinac H, Dzoljic E, Maksimovic J, Marinkovic J, Sipetic S, Kostic V.
Journal: Int J Neurosci. 2013 May;123(5):329-32.
PMID: 23270425

In this study, the researchers found that Parkinson’s Disease was also significantly associated to mumps, scarlet fever, influenza, and whooping cough as well as herpes simplex 1 infections. They found no association between Parkinson’s disease and Tuberculosis, measles or chickenpox though.

This result raises the tantalizing possibility that other viruses may also be involved with the onset of Parkinson’s disease (it should be added though that this study was based on only 110 people with Parkinson’s (compared with 220 controls) in one particular geographical location (Belgrade, Serbia)).

So different viruses may cause Parkinson’s disease?

We are not saying that either, but we would like to see more research on this topic.

And the situation may actually be more complicated than we think.

Recently, it has been reported that previous infection with flaviviruses (such as dengue) actually enhances the effect of Zika virus infect (Click here to read more on this). That is to say, a prior infection by one particular virus may exacerbate the infection of another virus. It could be that a previous infection by one virus increases that chance that a later infection by another virus – a particular combination of viral infections – may result in Parkinsonian symptoms (we are simply speculating here). 

Add to this complicated situation, the sheer number of unknown viruses. It is estimated that there are a minimum of 320,000 mammalian viruses still awaiting discovery (Click here for the source of this statistic), thus it is possible that additional unknown viruses may be involved with disease initiation for conditions like Parkinson’s disease.

A gang of unknown thieves in the night perhaps?

So what does it all mean?

Summing up: last week a new study was published that supported previous results that Hepatitis C viral infections could increase the risk of developing Parkinson’s disease. The results are important because they replicate previous findings from a different population of people.

The findings do not immediately mean that people with Hepatitis C are going to develop Parkinson’s disease, but it does suggest that they may be more vulnerable. The findings also suggest that more research is needed on the role of viral/infectious agents in the development of Parkinson’s disease.

We would certainly like to see more research in this area.

The banner for today’s post was sourced from Youtube

James: The man behind the disease (Part 1)

~ Simon ~ 7 Comments

jamesp-signature

As part of Parkinson’s awareness month, and in observation of the 200 year anniversary of the first description of Parkinson’s disease, today we begin a four part set of posts looking at the man who made that first observation: James Parkinson.

Each week we will present various aspects about the man and his life.

Much of the material presented here has been replicated from our sister site Searching 4 James – a (much neglected) website celebrating the man and documenting the search for his likeness. To date, no portrait or image of the man has ever been found.

L0068467 The Villager's Friend and Physician

Source: Wellcome Images.

In her excellent book “James Parkinson, 1755-1824: From Apothecary to General Practitioner“, Shirley Roberts wrote that other sources have proposed that the man standing in the middle of the image above, talking to the villagers, is James Parkinson. The image appeared in James’ book ‘The Villager’s friend and physician’ (published in 1800), but (and I think you’ll agree) it does not give us much to work with.

Unfortunately Shirley Roberts made no reference to the sources of the proposal, but it is as close as we get to a likeness of the man, as he died before the first photographs were taken and there is no recorded painting of him.

Most people think of James Parkinson as a medical practitioner given his association with the disease that bears his name. But this singular association doesn’t really do the man credit. His contributions to medicine went well beyond the first description of ‘Parkinson’s disease’ – for example, James also gave the western world our first description of gout – a form of inflammatory arthritis that he and his father both suffered.

In addition, James was a ‘rockstar’ to the geological community, producing one of the most well regarded series of textbooks on the subject at the time. He was a political radical who wrote many pamphlets under the pseudonym “Old Hubert” and his associations with other radicals almost got him ‘transported’ (shipped out to the colonies). He was also a social reformist, calling for parliamentary reforms and universal suffrage. And his religious devotion made him a prominent figure within his church.

In short, he was a very interesting chap, who lived in (and had an impact on) interesting times.

THE WORLD OF JAMES

Before discussing the man himself, we must consider the world that James Parkinson was born into and the era he lived through. It provides us with the context within which we can fully appreciate the contributions that he made (including those beyond medicine).

James Parkinson was born on the 11th April 1755.

In the grand scale of things, the mid 1700’s was the peak of the little ice age, the middle of the age of enlightenment, and (critically) the start of the industrial revolution. The world was:

  • Pre USA (1776)
  • Pre French Revolution (1789)
  • Pre public electricity supply (1881)
  • Pre Napoleon (1769)
  • Pre Darwin (1809)

In London, King George II was on the English throne (soon to be replaced by George III), and Westminster bridge had just been finished (1750). The population of the city was approx. 700,000, but most of them lived in terrible conditions.

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A view of London (1750). Source: Historic Cities

James was born into a world where 74% of children born in London failed to reach the age of five. The medical world still practised humoral medicine (black bile, yellow bile, phlegm, and blood). Diseases were believed to be caused by an accumulation of “poisons” in the body, cured by bleeding, enemas, and sweating or blistering. The medical profession was:

  • Pre Ed Jenner’s vaccine for smallpox (1796)
  • Pre Rene Laennec’s stethoscope (1816)
  • Pre nitrous oxide (1800) or ether anaesthesia (1846)
  • Pre germ theory (Ignaz Semmelweis, 1847)
  • Pre Joseph Lister’s anti-septic surgery (1863).

Amputations were by far the most frequent surgeries, but the survival rate of the procedure was only 40% (and remember, there was no anaesthesia).

James Parkinson was born at no. 1 Hoxton Square in the liberty of Hoxton in Shoreditch, Middlesex. He would live all but the last 2 years of his life at that address.

In 1755, Hoxton was simply a scattering of houses, orchards and market gardens that lay approximately half a mile from one of the north-east gates of the walls of London. During the 17-1800s, Hoxton Square was considered a very fashionable area and young James would have grown up surrounded by open, reasonably well to do areas.

The maps below were made shortly before James was born, and it suggests open spaces, gardens, orchards and fields surrounding Hoxton.

London-1746

London in 1746 (Shoreditch is indicated by the black square)
Source: John Roque’s Map

Shoreditch

A map of Hoxton in 1746 – no 1. Hoxton Square (red arrow)
and St Leonard Church (blue arrow) are indicated.

James was born at the onset of the industrial revolution and with London prospering there was an enormous increase in the number of inhabitants. As more and more of London’s real estate became dedicated to business purposes, the inhabitants began spilling out into the surrounding areas. With transportation still limited to foot and horse, the people who worked in London needed to stay close to their place of employment, thus areas like Hoxton began to fill up rapidly. In 1788, there were 34,700 people living in Hoxton (in 5730 houses), which grew to 109,200 people in 1851 (in 15,433 houses).

Thus, during James’ life, Hoxton went through a radical transition. The large homes, orchards and gardens of his youth gave way to factories and over-crowding. And as a result, the ‘Parkinson and Son’ practise that he ran with his father (and later his own son) changed from serving a middle class clientele to dealing predominantly with the working class. With the prosperity of the time, there came a new trend of philanthropy, giving rise to the building of hospitals and mental asylums (‘madhouses’). James was the medical attendant for one of these madhouses, Holly House (Hoxton road, Hoxton).

The maps below were made in 1830 (shortly after James died – 1824) and indicate tremendous growth and expansion in London and the Hoxton area with the loss of much of the open spaces.

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GREENWOOD MAP OF LONDON 1830 – Hoxton is indicated by the black square;
Tower of London (black arrow) and Westminster Abbey (red arrow) are also labelled – source: here

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 A map of Hoxton in 1830 – no 1. Hoxton Square (red arrow), St Leonard Church (blue arrow) and Holly House (Magenta arrow) are indicated.

THE FORMATIVE YEARS

James was baptised on the 29th of April 1755 in St Leonard’s church (Shoreditch) – the same church where he attended weekly services, got married, baptised his own children (and married some of them), and where he was eventually buried. The details of the baptism are recorded in the parish register, and read simply: James son of John and Mary Parkinson. Hoxton Square, Born 11th. Baptised 29th inst.

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St Leonard’s church (1827) – Source

St Leonard’s church formed one of the key pillars of James’ life, and he could readily view the spire of the church one just block away from no.1 Hoxton Square.

The Parkinson family never owned the house at no. 1 Hoxton Square, which was owned by one Joshua Jenning. The building they lived in is gone now, but it was still standing in 1910 when Prof Leonard George Rowntree, a lecturer at Johns Hopkins Medical School (Baltimore), visited it and described it as:

“The house is a plain old three story building facing the east, on the northwest corner of Hoxton Square. Behind the main building and connected with it is a smaller two-story one with a central door opening into the little side street. This apparently was Parkinson’s office. Behind this again is another smaller building which may have served as a laboratory, as a library, or perhaps as a museum. Leading up to the deeply set, black, massive looking front door are a stone walk and deeply worn stone steps. The house is only a few feet back from the street and before it stands an old iron fence.

Uninteresting though the exterior is, upon entering this building one is impressed at the large size of the rooms and with the evidences of the prosperity of other days. We see in almost every room great carved open fire-places of elaborate design, and between some rooms large connecting arches. The deep panelling of walls and ceiling which was formerly so much in vogue is well preserved in some of the rooms on the second floor. One is surprised to find such an interesting interior behind such an uninviting exterior”  

(Rowntree, 1912)

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An image of no.1 Hoxton Square – Source

James was the eldest surviving child of John (an apothecary and surgeon) and Mary Parkinson. James had two sisters who survived to adulthood, Margaret Townley Parkinson (born 3rd August,1759) and Mary Sedgewood (born 11th January, 1763).

Little is known about the formative years of James Parkinsons. From his own writings, we know that he had a solid education in Latin and Greek as well as chemistry, biology and mathematics. James was fortunate to grow up in a ‘comfortable, cultured home’ with ‘a medical atmosphere’. But a thriving literary, scientific, and religious atmosphere also existed in Hoxton square. No fewer than fifteen residents of the Square are biographized in the Dictionary of National Biography – a distinction not shared by any other London Square from that time. Nothing is known about where James received his education. His name does not appear on the registry of scholars of the well known public schools of London, such as St Paul’s, the charterhouse, Christ’s Hospital, Merchants Taylors – all of which were within walking distance of Hoxton Square. Private home schooling was very popular during this time. James certainly did not attend Cambridge or Oxford University.

At age 16, James began his training to be an apothecary. In accordance with an antiquated Elizabethan Act of Parliament, in order to become a surgeon a young man had to serve an apprenticeship of seven years. James was apprenticed to his father, but 20 years later he wrote that “no apprenticeship should be advisable except to a hospital”. James was extremely critical of the traditional methods used in the teaching of medicine at the time:

“The first four or five years are almost entirely appropriated to the compounding of medicines; the art of which,with every habit of necessary exactness, might just as well be obtained in as many months. The remaining years of his apprenticeship bring with them the acquisition of the art of bleeding, of dressing a blister, and, for the completion of the climax – of exhibiting an enema”  Parkinson, J. p32 (1800)

To further his training, James became one of the first medical students of the London Hospital Medical College (Whitechapel Road), founded by William Blizzard – surgeon of the Hospital. The college register records that he entered for training on Feb 20th 1776 when he was in his twentieth year. He was a ‘hospital pupil’ (or dresser) under Richard Grindall, FRS, at that time assistant surgeon. James remained for 6 months, but after this training he still felt ‘miserably ignorant’.

NPG D12199; Richard Grindall by William Daniell, after George Dance

Richard Grindall (1716-1795) – by William Daniell, (21 Aug 1793)  – Source

On 1st April 1784, James was examined and granted the grand diploma of the Company of Surgeons. He then joined his father in a practice, called “Parkinson and Son” (that practice was to last through 4 generations – approx. 80 years). Unfortunately, John Parkinson died only 6 years later, and James was left to manage the practice single-handedly. James was fortunate to take over his father’s prosperous practise as he noted that ‘a physician seldom obtains bread by his profession until he has no teeth left to eat it’. The clientele requiring the services of Parkinson and son, however, would change dramatically during James’s life. Parkinson’s and son’s evolved from a upper-middle class practise to an almost entirely working class practise by the time James passed on.

It says a great deal about the man that he did not move away from the community as it evolved (as many early inhabitants of Hoxton Square did).

On 21st May 1783, James married Mary Dale in St Leonard’s Church, by special license which was the custom of the upper and middle classes of that period. He was 25 and she was 23 years old. James’s friend Wakelin Welch Jr of Lympstone (Devon) acted as his best man (many years later, James’ book ‘Organic Remains of a Former World’ was dedicated to Welch).

According to the Family Pursuits website, Mary Dale (daughter of John Dale and Mary Hardy) was born 2nd September, 1757 in Shoreditch, Middlesex. Her family lived lived in Charles Square, Hoxton. Mary’s grandfather, Francis Dale (1650-1716), was an apothecary in Hoxton Old Town. He had three sons: Francis (also an apothecary), Thomas (1699-1750), and John (a silk merchant and Mary’s father). Her family not only had a medical history, but also geological. Mary’s grand uncle, Samuel Dale (1659-1739) was a keen botanist and one of the first to describe the fossils in the cliffs of Harwich (Essex).

 

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Samuel Dale (1659-1739) – Source: The Essex Field Club

Thus the marriage was most likely a good fit for James. Mary Parkinson would live a long life, dying on 28 March 1838 of typhus fever (Gardner-Thorpe, 2013). Together with James, she had six children, key amongst them was John William Keys Parkinson (born 11th July, 1785) who apprenticed to his father and would later become the ‘Son’ in ‘Parkinson and Son’ (and ultimately John’s son James Keys Parkinson would follow in this process).

In the next post of this series, we will look at James’ early years as a physician and his foray into political radicalism.

ADHD and Parkinson’s disease

~ Simon ~ 26 Comments

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The chemical dopamine plays a critical role in Parkinson’s disease.

It is also involved with the condition Attention deficit hyperactivity disorder, and recently researchers have been looking at whether there are any links between the two.

In today’s post we will look at what Attention deficit hyperactivity disorder is, how it relates to Parkinson’s disease, and what new research means for the community.

o-ADHD-facebook

Source: Huffington Post

We really have little idea about how Parkinson’s disease actually develops.

It could be kicked off by a virus or environmental factors or genetics…or perhaps a combination of these. We really don’t know, and it could vary from person to person.

There is a lot of speculation, however, as to what additional conditions could make one susceptible to Parkinson’s disease, even those conditions with early developmental onsets, such as autism (which we have previously written about – click here to see that post).

Recently researchers in Germany have asked if there is any connections between Parkinson’s and ADHD?

What is ADHD?

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental condition that begins in childhood and persists into adulthood in 60% of affected individuals.

It is classically characterised in the media by hyperactive children who struggle to concentrate and stay focused on what they are doing. They are often treated with drugs such as Methylphenidate (also known as ritalin). Methylphenidate acts by blocking a protein called the dopamine transporter, which is involved with reabsorbing the chemical dopamine back into the cell after it has performed it’s function.

1280px-Ritalin

Ritalin. Source: Wikipedia

So are there any connections between ADHD and Parkinson’s disease?

This is an interesting question.

While there have been no reported findings of increased (or decreased) frequency of Parkinson’s disease in people with ADHD (to our knowledge), there are actually several bits of evidence suggesting a connection between the two conditions, such as abnormalities in the substantia nigra:

substantia

Title: Structural abnormality of the substantia nigra in children with attention-deficit hyperactivity disorder
Authors: Romanos M, Weise D, Schliesser M, Schecklmann M, Löffler J, Warnke A, Gerlach M, Classen J, Mehler-Wex C.
Journal: J Psychiatry Neurosci. 2010 Jan;35(1):55-8.
PMID: 20040247               (This article is OPEN ACCESS if you would like to read it)

The substantia nigra is a structure in the brain where the dopamine neurons reside. In Parkinson’s disease, the dopamine neurons of the substantia nigra start to degenerate – 50% are lost by the time a person is diagnosed with the condition.

In this study, the researchers used a technique called echogenicity to examine the substantia nigra of 22 children with ADHD and 22 healthy controls. Echogenicity is the ‘ability to bounce an echo’. This sort of assessment measures the return of an ultrasound signal that is aimed at a structure.

The researchers found that the ADHD subjects had a larger substantia nigra area than the healthy controls – which apparently indicates dopamine dysfunction. This finding is similar to results that have been observed in Parkinson’s disease (Click here to read more regarding that study).

Another connection between the two conditions was recent research has shown that genetic variations in the PARK2 gene (also known as Parkin) contribute to the genetic susceptibility to ADHD.

Parkin title

Title: Genome-wide analysis of rare copy number variations reveals PARK2 as a candidate gene for attention-deficit/hyperactivity disorder.
Authors: Jarick I, Volckmar AL, Pütter C, Pechlivanis S, Nguyen TT, Dauvermann MR, Beck S, Albayrak Ö, Scherag S, Gilsbach S, Cichon S, Hoffmann P, Degenhardt F, Nöthen MM, Schreiber S, Wichmann HE, Jöckel KH, Heinrich J, Tiesler CM, Faraone SV, Walitza S, Sinzig J, Freitag C, Meyer J, Herpertz-Dahlmann B, Lehmkuhl G, Renner TJ, Warnke A, Romanos M, Lesch KP, Reif A, Schimmelmann BG, Hebebrand J, Scherag A, Hinney A.
Journal: Mol Psychiatry. 2014 Jan;19(1):115-21.
PMID: 23164820         (This article is OPEN ACCESS if you would like to read it)

There are about 20 genes that have been associated with Parkinson’s disease, and they are referred to as the PARK genes. Approximately 10-20% of people with Parkinson’s disease have a genetic variation in one or more of these PARK genes (we have discussed these before – click here to read that post). PARK2 is a gene called Parkin. Mutations in Parkin can result in an early-onset form of Parkinson’s disease. The Parkin gene produces a protein which plays an important role in removing old or sick mitochondria (we discussed this in our previous post – click here to read that post).

In this report, the researchers conducted a genetic sequencing study on 489 young subjects with ADHD (average age 11 years old) and 1285 control individuals. They replicated the study with a similar sized population of people affected by ADHD and control subjects, and in both studies they found that certain deletions and replications in the Parkin gene influences susceptibility to ADHD – two of the genetic variations were found in 335 of the ADHD cases and none in 2026 healthy controls (from both sets of studies).

So there are are some interesting possible connections between  ADHD and Parkinson’s disease.

And what has the recent research from the German scientists found?

In this study, the researchers have looked at additional genetic variations that have been suggested to infer susceptibility to ADHD.

adhd

Title: No genetic association between attention-deficit/hyperactivity disorder (ADHD) and Parkinson’s disease in nine ADHD candidate SNPs
Authors: Geissler JM; International Parkinson Disease Genomics Consortium members., Romanos M, Gerlach M, Berg D, Schulte C.
Journal: Atten Defic Hyperact Disord. 2017 Feb 7. doi: 10.1007/s12402-017-0219-8. [Epub ahead of print]
PMID: 28176268

The researchers analysed nine genetic variations in seven genes:

  • one variant in the gene synaptosomal-associated protein, 25kDa1 (SNAP25)
  • one variant in the gene dopamine transporter (DAT; also known as SLC6A3)
  • one variant in the gene dopamine receptor D4 (DRD4)
  • one variant in the gene serotonin receptor 1B (HTR1B)
  • three mutations in cadherin 13 (CDH13)
  • one mutation located within the gene tryptophan hydroxylase 2 (TPH2)
  • one mutation located within the gene noradrenaline transporter (SLC6A2)

These genetic variations were assessed in 5333 cases of Parkinson’s disease and 12,019 healthy controls. The researchers found no association between any of the genetic variants and Parkinson’s disease. This finding lead the investigators to conclude that these genetic alterations associated with ADHD do not play a substantial role in increasing the risk of developing Parkinson’s disease.

Have ADHD medications ever been tested in Parkinson’s disease?

Yes.

Given the association of both ADHD and Parkinson’s disease with altered dopamine processing in the brain, a clinical trial of ritalin in Parkinson’s disease was set up and run in 2006 (Click here to read more about that trial). The results of the trial were published in 2007:

 

Ritalin title

Title: Effects of methylphenidate on response to oral levodopa: a double-blind clinical trial.
Authors: Nutt JG, Carter JH, Carlson NE.
Journal: Arch Neurol. 2007 Mar;64(3):319-23.
PMID: 17353373       (This article is OPEN ACCESS if you would like to read it)

In this study, the researchers recruited 12 people with Parkinson’s disease and examined their response to 0.4 mg/kg of ritalin – given 3 times per day – in conjunction with their normal anti-Parkinsonian medication (L-dopa). They then tested the subjects with either ritalin or a placebo control and failed to find any clinically significant augmentation of L-dopa treatment from the co-administration of ritalin.

What does it all mean?

So summing up: both Attention deficit hyperactivity disorder (ADHD) and Parkinson’s disease are associated with changes in the processing of the brain chemical dopamine. There are loose connections between the two conditions, but nothing definitive.

It will be interesting to follow up some of the individuals affected by ADHD, to determine if they ultimately go on to develop Parkinson’s (particularly those with Parkin mutations/genetic variants). But until then, the connection between these two conditions is speculative at best.

The banner for today’s post was sourced from Youtube

Resveratrol: From the folks who brought you Nilotinib

~ Simon ~ 11 Comments

 

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Recently the results of a small clinical study looking at Resveratrol in Alzheimer’s disease were published. Resveratrol has long been touted as a miracle ingredient in red wine, and has shown potential in animal models of Parkinson’s disease, but it has never been clinically tested.

Is it time for a clinical trial?

In today’s post we will review the new clinical results and discuss what they could mean for Parkinson’s disease.

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From chemical to wine – Resveratrol. Source: Youtube

In 2006, there was a research article published in the prestigious journal Nature about a chemical called resveratrol that improved the health and survival of mice on a high-calorie diet (Click here for the press release).

Wine2
Title: Resveratrol improves health and survival of mice on a high-calorie diet.
Authors: Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, Prabhu VV, Allard JS, Lopez-Lluch G, Lewis K, Pistell PJ, Poosala S, Becker KG, Boss O, Gwinn D, Wang M, Ramaswamy S, Fishbein KW, Spencer RG, Lakatta EG, Le Couteur D, Shaw RJ, Navas P, Puigserver P, Ingram DK, de Cabo R, Sinclair DA.
Journal: Nature. 2006 Nov 16;444(7117):337-42.
PMID: 17086191          (This article is OPEN ACCESS if you would like to read it)

In this study, the investigators placed middle-aged (one-year-old) mice on either a standard diet or a high-calorie diet (with 60% of calories coming from fat). The mice were maintained on this diet for the remainder of their lives. Some of the high-calorie diet mice were also placed on resveratrol (20mg/kg per day).

After 6 months of this treatment, the researchers found that resveratrol increased survival of the mice and insulin sensitivity. Resveratrol treatment also improved mitochondria activity and motor performance in the mice. They saw a clear trend towards increased survival and insulin sensitivity.

The report caused a quite a bit of excitement – suddenly there was the possibility that we could eat anything we wanted and this amazing chemical would safe us from any negative consequences.

Grape

Source: Nature

That report was proceeded by numerous studies demonstrating that resveratrol could extend the life-span of various micro-organisms, and it was achieving this by activating a family of genes called sirtuins (specifically Sir1 and Sir2) (Click here, here and here for more on this).

Subsequent to these reports, there have been numerous scientific publications suggesting that resveratrol is capable of all manner of biological miracles.

Wow! So what is resveratrol?

grapes

Do you prefer your wine in pill form? Source: Patagonia

Resveratrol is a chemical that belongs to a group of compounds called polyphenols. They are believed to act like antioxidants. Numerous plants produce polyphenols in response to injury or when the plant is under attack by pathogens (microbial infections).

Fruit are a particularly good source of resveratrol, particularly the skins of grapes, blueberries, raspberries, mulberries and lingonberries. One issue with fruit as a source of resveratrol, however, is that tests in rodents have shown that less than 5% of the oral dose was observed as free resveratrol in blood plasma (Source). This has lead to the extremely popular idea of taking resveratrol in the form of wine, in the hope that it could have higher bioavailability compared to resveratrol in pill form. Red wines have the highest levels of Resveratrol in their skins (particularly Mabec, Petite Sirah, St. Laurent, and pinot noir). This is because red wine is fermented with grape skins longer than is white wine, thus red wine contains more resveratrol.

EDITOR’S NOTE: Sorry to rain on the parade, but it is important to note here that red wine actually contains only small amounts of resveratrol – less than 3-6 mg per bottle of red wine (750ml). Thus, one would need to drink a great deal of red wine per day to get enough resveratrol (the beneficial effects observed in the mouse study described above required 20mg/kg of resveratrol per day. For a person weighting 80kg, this would equate to 1.6g per day or approximately 250 750ml bottles). 

We would like to suggest that consuming red wine would NOT be the most efficient way of absorbing resveratrol. And obviously we DO NOT recommend any readers attempt to drink 250 bottles per day (if that is even possible). 

The recommended daily dose of resveratrol should not exceed 250 mg per day over the long term (Source). Resveratrol might increase the risk of bleeding in people with bleeding disorders. And we recommend discussing any change in treatment regimes with your doctor before starting.

So what did they find in the Alzheimer’s clinical study?

Well, the report we will look at today is actually a follow-on to published results from a phase 2/safety clinical trial that were reported in 2015:

trial.jpg

Title: A randomized, double-blind, placebo-controlled trial of resveratrol for Alzheimer disease.
Authors: Turner RS, Thomas RG, Craft S, van Dyck CH, Mintzer J, Reynolds BA, Brewer JB, Rissman RA, Raman R, Aisen PS; Alzheimer’s Disease Cooperative Study.
Title: Neurology. 2015 Oct 20;85(16):1383-91.
PMID: 26362286          (This article is OPEN ACCESS if you would like to read it)

The researchers behind the study are associated with the Georgetown research group that conducted the initial Nilotinib clinical study in Parkinson’s disease (Click here for our post on this).

The investigators conducted a randomized, placebo-controlled, double-blind, multi-center phase 2 trial of resveratrol in individuals with mild to moderate Alzheimer disease. The study lasted 52 weeks and involved 119 individuals who were randomly assigned to either placebo or resveratrol 500 mg orally daily treatment.

EDITOR’S NOTE: We appreciate that is daily dose exceeds the recommended daily dose mentioned above, but it is important to remember that the participants involved in this study were being closely monitored by the study investigators.

Brain imaging and samples of cerebrospinal fluid (the liquid within which the brain sits) were collected at the start of the study and after completion of treatment.

The most important result of the study was that resveratrol was safe and well-tolerated. The most common side effect was feeling nausea and diarrhea in approximately 42% of individuals taking resveratrol (curiously 33% of the participants blindly taking the placebo reported the same thing). There was also a weight loss effect between the groups, with the placebo group gaining 0.5kg on average, while the resveratrol treated group lost 1kg on average.

The second important take home message is that resveratrol crossed the blood–brain barrier in humans. The blood brain barrier prevents many compounds from having any effect in the brain, but it does not stop resveratrol.

The investigators initially found no effects of resveratrol treatment in various Alzheimer’s markers in the cerebrospinal fluid. Not did they see any effect in brain scans, cognitive testing, or glucose/insulin metabolism. The authors were cautious about their conclusions based on these results, however, as the study was statistically underpowered (that is to say, there were not enough participants in the various groups) to detect clinical benefits. They recommended a larger study to determine whether resveratrol is actually beneficial.

While exploring the idea of a larger study, the researchers have re-analysed some of the data, and that brings us to the report we want to review today:

moussa

Title: Resveratrol regulates neuro-inflammation and induces adaptive immunity in Alzheimer’s disease.
Authors: Moussa C, Hebron M, Huang X, Ahn J, Rissman RA, Aisen PS, Turner RS.
Journal: J Neuroinflammation. 2017 Jan 3;14(1):1. doi: 10.1186/s12974-016-0779-0.
PMID: 28086917       (This article is OPEN ACCESS if you would like to read it)

In this report, the investigators conducted a retrospective study re-examining the cerebrospinal fluid and blood plasma samples from a subset of subjects involved in the clinical study described above. In this study, they only looked at the subjects who started with very low levels in the cerebrospinal fluid of a protein called Aβ42.

Amyloid beta (or Aβ) is the bad boy/trouble maker of Alzheimer’s disease; considered to be critically involved in the disease. A fragment of this protein (called Aβ42) begin clustering in the brains of people with Alzheimer’s disease and as a result, low levels of Aβ42 in cerebrospinal fluid have been associated with increased risk of Alzheimer’s disease and considered a possible biomarker of the condition (Click here to read more on this).

The resveratrol study investigators collected all of the data from subjects with cerebrospinal fluid levels of Aβ42 less than 600 ng/ml at the start of the study. This selection criteria gave them 19 resveratrol-treated and 19 placebo-treated subjects.

In this subset re-analysis study, resveratrol treatment appears to have slowed the decline in cognitive test scores (the mini-mental status examination), as well as benefiting activities of daily living scores and cerebrospinal fluid levels of Aβ42.

One of the most striking results from this study is the significant decrease observed in the cerebrospinal fluid levels of a protein called Matrix metallopeptidase 9 (or MMP9) after resveratrol treatment. MMP9 is slowly emerged as an important player in several neurodegenerative conditions, including Parkinson’s disease (Click here to read more on this). Thus the decline observed is very interesting.

This re-analysis indicates beneficial effects in some cases of Alzheimer’s as a result of taking resveratrol over 52 weeks. The researchers concluded that the findings of this re-analysis support the idea of a larger follow-up study of resveratrol in people with Alzheimer’s disease.

Ok, but what research has been done on resveratrol in Parkinson’s disease?

Yes, good question.

One of the earliest studies looking at resveratrol in Parkinson’s disease was this one:

Reserv
Title: Neuroprotective effect of resveratrol on 6-OHDA-induced Parkinson’s disease in rats.
Authors: Jin F, Wu Q, Lu YF, Gong QH, Shi JS.
Journal: Eur J Pharmacol. 2008 Dec 14;600(1-3):78-82.
PMID: 18940189

In this study, the researchers used a classical rodent model of Parkinson’s disease (using the neurotoxin 6-OHDA). One week after inducing Parkinson’s disease, the investigators gave the animals either a placebo or resveratrol (at doses of 10, 20 or 40 mg/kg). This treatment regime was given daily for 10 weeks and the animals were examined behaviourally during that time.

The researchers found that resveratrol improved motor performance in the treated animals, with them demonstrating significant results as early as 2 weeks after starting treatment. Resveratrol also reduced signs of cell death in the brain. The investigators concluded that resveratrol exerts a neuroprotective effect in this model of Parkinson’s disease.

Similar results have been seen in other rodent models of Parkinson’s disease (Click here and here to read more).

Subsequent studies have also looked at what effect resveratrol could be having on the Parkinson’s disease associated protein alpha synuclein, such as this report:

PD-title

Title: Effect of resveratrol on mitochondrial function: implications in parkin-associated familiarParkinson’s disease.
Authors: Ferretta A, Gaballo A, Tanzarella P, Piccoli C, Capitanio N, Nico B, Annese T, Di Paola M, Dell’aquila C, De Mari M, Ferranini E, Bonifati V, Pacelli C, Cocco T.
Journal: Biochim Biophys Acta. 2014 Jul;1842(7):902-15.
PMID: 24582596                     (This article is OPEN ACCESS if you would like to read it)

 

In this study, the investigators collected skin cells from people with PARK2 associated Parkinson’s disease.

What is PARK2 associated Parkinson’s disease?

There are about 20 genes that have been associated with Parkinson’s disease, and they are referred to as the PARK genes. Approximately 10-20% of people with Parkinson’s disease have a genetic variation in one or more of these PARK genes (we have discussed these before – click here to read that post).

PARK2 is a gene called Parkin. Mutations in Parkin can result in an early-onset form of Parkinson’s disease. The Parkin gene produces a protein which plays an important role in removing old or sick mitochondria.

Hang on a second. Remind me again: what are mitochondria?

We have previously written about mitochondria (click here to read that post). Mitochondria are the power house of each cell. They keep the lights on. Without them, the lights go out and the cell dies.

Mitochondria

Mitochondria and their location in the cell. Source: NCBI

You may remember from high school biology class that mitochondria are bean-shaped objects within the cell. They convert energy from food into Adenosine Triphosphate (or ATP). ATP is the fuel which cells run on. Given their critical role in energy supply, mitochondria are plentiful and highly organised within the cell, being moved around to wherever they are needed.

Another Parkinson’s associated protein, Pink1 (which we have discussed before – click here to read that post), binds to dysfunctional mitochondria and then grabs Parkin protein which signals for the mitochondria to be disposed of. This process is an essential part of the cell’s garbage disposal system.

Park2 mutations associated with early onset Parkinson disease cause the old/sick mitochondria are not disposed of correctly and they simply pile up making the cell sick. The researchers that collected the skin cells from people with PARK2 associated Parkinson’s disease found that resveratrol treatment partially rescued the mitochondrial defects in the cells. The results obtained from these skin cells derived from people with early-onset Parkinson’s disease suggest that resveratrol may have potential clinical application.

Thus it would be interesting (and perhaps time) to design a clinical study to test resveratrol in people with PARK2 associated Parkinson’s disease.

So why don’t we have a clinical trial?

Resveratrol is a chemical that falls into the basket of un-patentable drugs. This means that big drug companies are not interested in testing it in an expensive series of clinical trials because they can not guarantee that they will make any money on their investment.

There was, however, a company set up in 2004 by the researchers behind the original resveratrol Nature journal report (discussed at the top of this post). That company was called “Sirtris Pharmaceuticals”.

e4d4a0ddab6419c9de2bd8ca4f199e0c

Source: Crunchbase

Sirtris identified compounds that could activate the sirtuins family of genes, and they began testing them. They eventually found a compound called SRT501 which they proposed was more stable and 4 times more potent than resveratrol. The company went public in 2007, and was subsequently bought by the pharmaceutical company GlaxoSmithKline in 2008 for $720 million.

Sirtris_rm

Source: Xconomy

From there, however, the story for SRT501… goes a little off track.

In 2010, GlaxoSmithKline stopped any further development of SRT501, and it is believed that this decision was due to renal problems. Earlier that year the company had suspended a Phase 2 trial of SRT501 in a type of cancer (multiple myeloma) because some participants in the trial developed kidney failure (Click here to read more).

Then in 2013, GlaxoSmithKline shut down Sirtris Pharmaceuticals completely, but indicated that they would be following up on many of Sirtris’s other sirtuins-activating compounds (Click here to read more on this).

Whether any of those compounds are going to be tested on Parkinson’s disease is yet to be determined.

What we do know is that the Michael J Fox foundation funded a study in this area in 2008 (Click here to read more on this), but we are yet to see the results of that research.

We’ll let you know when we hear of anything.

So what does it all mean?

Summing up: Resveratrol is a chemical found in the skin of grapes and berries, which has been shown to display positive properties in models of neurodegeneration. A recent double blind phase II efficacy trial suggests that resveratrol may be having positive benefits in Alzheimer’s disease.

Preclinical research suggests that resveratrol treatment could also have beneficial effects in Parkinson’s disease. It would be interesting to see what effect resveratrol would have on Parkinson’s disease in a clinical study.

Perhaps we should have a chat to the good folks at ‘CliniCrowd‘ who are investigating Mannitol for Parkinson’s disease (Click here to read more about this). Maybe they would be interested in resveratrol for Parkinson’s disease.

ONE LAST EDITOR’S NOTE: Under absolutely no circumstances should anyone reading this material consider it medical advice. The material provided here is for educational purposes only. Before considering or attempting any change in your treatment regime, PLEASE consult with your doctor or neurologist. SoPD can not be held responsible for actions taken based on the information provided here. 

The banner for today’s post was sourced from VisitCalifornia

A yeast model of Parkinson’s disease

~ Simon ~ 4 Comments

yeast-cell

When I say the word ‘yeast’, you might think of making bread or beer.

One does not automatically think of Parkinson’s disease.

But yeast has actually been incredibly useful in enhancing our understanding of the genetics of Parkinson’s disease, and may well now provide us with novel treatments for the condition. In today’s post we will discuss how yeast research is leading the way for Parkinson’s disease.

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Prof Susan Lindquist. Source: WallStreetJournal

It was with sadness that we heard about the passing of Prof Susan Lindquist in October last year. She was truly a pioneer in the field of molecular biology. In addition to advancing our understanding of gene functioning in degenerative diseases like Parkinson’s disease and Alzheimer’s, she also started a company, Yumanity, which is currently testing new drugs to tackle these conditions. Hopefully her legacy will have enormous impact for the millions of people around the world struggling with these conditions.

And that legacy all started with a bold (some even called it ‘crazy’) idea.

It involved yeast.

What is yeast?

Quite possibly the earliest domesticated species, yeast is a single-celled microorganism, traditionally classified as a member of the fungus kingdom. The evolutionary lineage of yeast dates back hundreds of millions of years old and there are at least 1500 species of yeast (Source: Wikipedia).

cell

The cellular structure of yeast. Source: Biocourseware

More importantly, yeast is one of the most centrally important model organisms used in modern biological research, representing one of the most thoroughly researched organisms in the world.

We know more about the biology of yeast than we do about ourselves!

And this statement is made further evident as researchers use yeast to produce the world’s first synthetic organism (an organism for which the genome has been designed or engineered). By the end of 2017, the Synthetic Yeast 2.0 consortium plans to have produced a new form of yeast in which all 16 chromosomes will have been made in the lab (for more on this, read this STAT article).

Why do scientists like studying yeast?

The main reason is that yeast cells are very similar to human cells, but they grow a lot faster (human cells on average divide a rate of about once every 12 hours, while yeast cells divide every two hours). Yeast is similar to human cells in that it has all of the eukaryote structures, including a nucleus, cytoplasm, and mitochondria (eukaryote meaning a cell with a nucleus).

Yeast has played a fundamental role in many major scientific discoveries since the early 1900s. In 1907, German scientist Edward Buchner won the Nobel Prize in Chemistry for research involving yeast extract and fermentation. Ninety one years later (2006), Roger D. Kornberg won the same prize for his work on DNA transcription using yeast.

Yeast was the first eukaryote to have its genome (DNA) fully sequenced (in 1996). Yeast is literally leading the way in biological research.

So what has this got to do with Parkinson’s disease?

This is where Prof Susan Lindquist comes into the story.

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Source: Youtube

In the early 2000s, she suggested the idea of using yeast to look at neurodegenerative conditions like Parkinson’s disease. It was a wild concept. Talking to the New York Times in 2007, she said “Even people in my laboratory thought we were crazy to try to study neurodegenerative diseases with a yeast cell. It’s not a neuron”.

But they persevered and in 2003 they published this research report in the journal Science:

yeast

Title: Yeast genes that enhance the toxicity of a mutant huntingtin fragment or alpha-synuclein.
Authors: Willingham S, Outeiro TF, DeVit MJ, Lindquist SL, Muchowski PJ.
Journal: Science. 2003; 302(5651):1769-72.
PMID: 14657499

In this study, the researchers conducted a genome-wide screens of mutant genes in yeast to identify genes that enhanced the toxic effects of the mutant huntingtin gene or alpha-synuclein protein. That is to say, they randomly mutated (made un-operational) just one gene per yeast cell, and these yeast cells either had the mutant huntingtin gene (which causes the neurodegenerative condition of Huntington’s disease) or too much alpha synuclein (which causes protein clumping in the yeast cells). Using this approach, they could determine which genes were responsible for increasing the negative effects of the mutant huntington gene or the alpha synuclein protein.

Of the 4850 yeast genes that the researcher mutated (and can we just point out that that is A LOT of work!!!), 52 were identified that exaggerated the affect of the mutant huntingtin gene and 86 increased sensitivity to alpha-synuclein (curiously, only one mutant gene resulted in increased sensitivity to both).

When they looked at the known functions of 86 genes that were increasing the sensitivity to alpha synuclein, the researchers found that most of them were involved in the processes of lipid metabolism (the synthesis and degradation of lipids) and vesicle-mediated transport (this occurs at the tips of neural branches – where alpha synuclein is located). Alpha synuclein is known to be involved with lipid metabolism (Click here and here for more on this). This reenforced the belief with the researchers that yeast could be used to assess disease relevant pathways – this study gave them the ‘proof of concept’.

In addition, the majority of the genes had human ‘orthologs’ (genes in different species that evolved from a common ancestral gene), meaning that the findings of yeast studies could potentially be translated to higher order creatures, like humans. The researchers concluded that they had found cell autonomous genes that are relevant to Parkinson’s disease.

With the publication of this work, people in Prof Lindquist’s lab were probably thinking the idea wasn’t so crazy anymore.

And this first publication led to many more, such as this report which was published in the same journal in 2006:

Linds
Title: Alpha-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson’s models.
Authors: Cooper AA, Gitler AD, Cashikar A, Haynes CM, Hill KJ, Bhullar B, Liu K, Xu K, Strathearn KE, Liu F, Cao S, Caldwell KA, Caldwell GA, Marsischky G, Kolodner RD, Labaer J, Rochet JC, Bonini NM, Lindquist S.
Journal: Science. 2006 Jul 21;313(5785):324-8.
PMID: 16794039      (This article is OPEN ACCESS if you would like to read it)

In this study, the researchers doubled the amount of alpha synuclein that yeast cells produce and they observed that the cell stopped growing and started to die. They then looked at the earliest cellular events following theover production of alpha synuclein and they noticed that there was a blockage in the endoplasmic reticulum (ER)-to-Golgi vesicular trafficking.

Yes, I know what you are going to ask: What is ER-to-Golgi vesicular trafficking?

The endoplasmic reticulum (or ER) is a network of tubules connected to the nucleus. It is involved in the production of proteins and lipids, which are then transported to the Golgi apparatus which then modifies them, sorts them and and packs them into small bags called vesicles. These vesicles can then be taken to the cell membrane where the proteins are released to do their jobs.

ergolgi

The ER to Golgi pathway. Source: Welkescience

Now the fact that too much alpha synuclein was blocking this pathway was interesting, but the researchers wanted to go further. They conducted another genome-wide screens of genes in yeast to identify genes that could rescue this blockage – BUT this time, instead of mutating genes, the researchers randomly over produced one protein (and there was 3000 of them!!!) in each cell. Because the overproduction of alpha synuclein kills the yeast cells, all the researchers had to do was wait until the end of the experiment and determine which protein was over produced in the surviving cells.

And this led them to a protein called RAB1.

RAB1 is a protein that is critical to the transportation of proteins in cells. The researchers next tested the ability of RAB1 to rescue dopamine cells in Drosophila (flies), Caenorhabditis elegans (microscopic worms), and cell culture models of Parkinson’s disease and they found that it was able to rescue the cells in all three cases. While this result was very interesting, it also provided full validation of the approach that Prof Lindquist and her colleagues were taking using yeast cells to find new therapies for neurodegenerative conditions, like Parkinson’s disease.

But Prof Lindquist and her colleagues didn’t stop there.

Over the next decade numerous research reports were published taking advantage of this approach, including these two reports which appeared back-to-back in the journal Science:

lindq1

Title: Identification and rescue of α-synuclein toxicity in Parkinson patient-derived neurons.
Authors: Chung CY, Khurana V, Auluck PK, Tardiff DF, Mazzulli JR, Soldner F, Baru V, Lou Y, Freyzon Y, Cho S, Mungenast AE, Muffat J, Mitalipova M, Pluth MD, Jui NT, Schüle B, Lippard SJ, Tsai LH, Krainc D, Buchwald SL, Jaenisch R, Lindquist S.
Journal: Science. 2013 Nov 22;342(6161):983-7.
PMID: 24158904

And:

lindq2

Title: Yeast reveal a “druggable” Rsp5/Nedd4 network that ameliorates α-synuclein toxicity in neurons.
Authors: Tardiff DF, Jui NT, Khurana V, Tambe MA, Thompson ML, Chung CY, Kamadurai HB, Kim HT, Lancaster AK, Caldwell KA, Caldwell GA, Rochet JC, Buchwald SL, Lindquist S.
Journal: Science. 2013 Nov 22;342(6161):979-83.
PMID: 24158909

In these reports, Prof Lindquist and colleagues tested whether some of the proteins that had come up in their various screens could actually have positive benefits in human cells, specifically induced pluripotent stem (iPS) cells (which we have discussed before – click here to read that post). The researchers grew brains cells (neurons and glial cells) from the iPS cells derived from people who suffered from Parkinson’s disease with dementia. These cells exhibited a number of features that indicated that they were not healthy. From their yeast screens, the researchers identified a protein called Nedd4 that reversed the pathologic features in these neurons.

Nedd4 is an E3 ubiquitin-protein ligase, which is a protein involved in the removal of old or damaged proteins from a cell. It is part of the garbage disposal process. Importantly, Nedd4 has been shown to label alpha synuclein for disposal (Click here to read more about this) and it is also present in Lewy Bodies – the circular clusters of proteins present in the brains of people with Parkinson’s disease. Importantly, it is a ‘druggable’ target. Nedd4 has been considered a therapeutic target for cancer (Click here to read more on this).

More recently (and following the passing of Prof Lindquist) the group has published two research reports back-to-back in the journal Cell Systems:

yeast-3

Title: Genome-Scale Networks Link Neurodegenerative Disease Genes to α-Synuclein through Specific Molecular Pathways.
Authors: Khurana V, Peng J, Chung CY, Auluck PK, Fanning S, Tardiff DF, Bartels T, Koeva M, Eichhorn SW, Benyamini H, Lou Y, Nutter-Upham A, Baru V, Freyzon Y, Tuncbag N, Costanzo M, San Luis BJ, Schöndorf DC, Barrasa MI, Ehsani S, Sanjana N, Zhong Q, Gasser T, Bartel DP, Vidal M, Deleidi M, Boone C, Fraenkel E, Berger B, Lindquist S.
Journal: Cell Syst. 2017 Jan 25. pii: S2405-4712(16)30445-8.
PMID: 28131822        (This article is OPEN ACCESS if you would like to read it)

And:

chung2

Title: In Situ Peroxidase Labeling and Mass-Spectrometry Connects Alpha-Synuclein Directly to Endocytic Trafficking and mRNA Metabolism in Neurons.
Authors: Chung CY, Khurana V, Yi S, Sahni N, Loh KH, Auluck PK, Baru V, Udeshi ND, Freyzon Y, Carr SA, Hill DE, Vidal M, Ting AY, Lindquist S.
Journal: Cell Syst. 2017 Jan 25. pii: S2405-4712(17)30002-9.
PMID: 28131823

In these reports, Prof Lindquist and colleagues systematically mapped out molecular pathways underlying the toxic effects of alpha-synuclein. They applied their yeast derived 332 genes that impact alpha-synuclein toxicity, and linked them to multiple Parkinson’s-associated genes and druggable targets, using software called TransposeNet.

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Source: Cell

The investigators then validated some of the connections in human iPS cells derived from people with Parkinson’s disease, confirming that some of the Parkinson’s disease-related genetic interactions observed in yeast are ‘conserved’ (that is maintained across evolution) to humans. And these findings fully vindicated Prof Lindquist’s ‘crazy’ idea of using yeast cells to investigate neurodegenerative disease.

In the second report, the researchers identified 225 proteins in close physical proximity to alpha-synuclein in neurons using a new technique (called ascorbate peroxidase (APEX) labeling – let’s just say it’s complicated, but if you’d like to read more about it, Click here). Many of those 225 proteins were well known to the researchers being involved with activities in vesicles and synaptic terminals, where alpha synuclein is often found. But the researchers also found microtubule-associated proteins (including tau) rubbing shoulders with alpha-synuclein, as well as proteins involved with mRNA binding, processing, and translation (which they were not expecting). Thus, not only has Prof Lindquist’s yeast model of Parkinson’s disease provided us with novel therapeutic targets, but also opened new avenues of research related to alpha synuclein functioning.

 

And there is now a ‘yeast’ biotech company?

It is called Yumanity.

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Yumanity. Source: ScientificAmerican

Started in December 2014, with $45 million in funding, Yumanity is focused on determining new targets for neurodegenerative conditions in yeast cells, testing those new targets in human cells, and then moving towards clinical trials with the best candidates. To date, they have not announced any clinical trial candidates, but they working on compounds that are targeting the NEDD4 pathway in Parkinson disease (discussed above). We will be watching this company with great interest.

So what does it all mean?

Back in the early 2000s, Prof Lindquist and her team asked a simple but strange question:

Can we use our knowledge of yeast genetics to study neurodegeneration?

We now know that the answer is ‘yes’. The small single cell organism that most of us associate with baking and beer, shares enough genetics with us that we can use it as an assay for investigating molecular pathways involved with diseases of the brain. And in the not so distant future, this simple little organism may be providing us with new treatments and therapies for those diseases.

As we suggested at the start of this post, Prof Lindquist has left an amazing legacy. If Yumanity can move a new drug into clinical trials for Parkinson’s disease, it will only further strengthen that legacy.

Susan Lee Lindquist – June 5, 1949 to October 27, 2016

The banner for today’s post was sourced from NewEuropeans

The Journal of Parkinson’s disease – special issue

~ Simon ~ Leave a comment

JPD_logo_editors

Our policy at the SoPD is not to advertise or endorse commercial products or services. This is to avoid any ethical or conflict of interest situations.

Every now and then, however, we see something that we believe will be of interest and value to the Parkinson’s community…aaand we bend our policy rule book.

Today the Journal of Parkinson’s disease released a “200 years of Parkinson’s disease” OPEN ACCESS special issue of their journal which highlights some of the major discoveries in the field of Parkinson’s disease research.

Critically, the articles provide insights into how the discoveries were made, and they are written by some of the biggest names in the Parkinson’s research community (many of whom were actually there when the discoveries were made).

The issue has articles dealing with topics including:

Click here to see all of the articles in this special issue.

We fully recommend readers take advantage of this OPEN ACCESS issue and learn about how some of these great discoveries were made.

Happy reading.

Full disclosure: The Journal of Parkinson’s disease is a product of IOS Press. The SoPD has not been approached by or made any offers to IOS Press or anyone at the Journal of Parkinson’s disease. We merely thought that the material in this particular OPEN ACCESS issue would be of interest to our readers.

The banner for today’s post was sourced from the Journal of Parkinson’s disease

HIV and Parkinson’s disease

~ Simon ~ 5 Comments

hiv-aids-definition2

 

I was recently made aware of an interesting fact:

Approximately 5% of people with Human immunodeficiency virus (HIV) infections develop Parkinson’s disease-like features.

Why is this?

In today’s post we will try to understand what is going on, and what it may mean for Parkinson’s disease.

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HIV (in green) budding (being released) from a blood cell (lymphocyte). Source: Wikipedia

Ok, let’s start at the beginning:

What is HIV?

Human immunodeficiency virus (or HIV) – as the name suggests – is the virus.

It causes the infection which gives rise to Acquired Immune Deficiency Syndrome (or AIDS). AIDS is a progressive failure of the immune system – the body loses its ability to fight infections. Without treatment, average survival period after infection with HIV is between 9 – 12 years.

HIV can be spread by the transfer of bodily fluids, such as blood and semen. The World Health Organisation (WHO) has estimated that approximately 36.9 million people worldwide were living with HIV/AIDS at the end of 2014 (that is equivalent to the entire population of Canada!).

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The structure of the HIV virus. Source: Wikipedia

Does HIV affect the brain?

Yes.

At postmortem examinations, less than 10% of the brains from HIV infected individuals are histologically normal (Source).

HIV is a member of the lentivirus family of viruses, which readily infect immune cells (such as blood cells). HIV can also infect other types of cells though, including those in the brain. HIV will usually enter the central nervous system within the first month following infection. It enters the brain via infected blood cells which come into contact with brain ‘immune system/helper’ cells such as microglia and macrophages at the blood-brain-barrier.

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How HIV enters the brain. Source: Disease Models and Mechanisms

HIV can also infect astrocytes (albeit at a lower frequency than microglia and macrophages), by direct cell-cell contact with infected T cells (blood cells) at the blood-brain-barrier (No. 1 in the image above). After infecting astrocytes, there is dysfunction in the astrocyte and it will no longer be so supportive to the local neurons (No. 2 in the image above). Once inside the brain, HIV-infected macrophages will allow for infection of other macrophages and microglia (No. 3 in the image above), and all together these HIV-infected astrocytes and microglia will cause damage to neurons by releasing viral proteins (two in particular, called Tat and gp120) and additional nasty chemicals which are bad for the neurons (No. 4 in the image above). Finally, as the disease progresses, the protective layer of the blood-brain-barrier becomes compromised and HIV-infected T cells eventually enter the brain and they cause damage to neurons by releasing pro-inflammatory chemicals (making the environment harsh for neurons).

There is remarkably little evidence of HIV actually infecting neurons (Click here for a review on this), so any cell loss in the brain that is associated with HIV does not result from neurons themselves being infected. This may be due to the fact that neurons do not have the HIV receptors (such as CD4) on their cell membrane. Similarly, oligodendrocytes (a supporting cell) does not appear to be easily infected by HIV. The bulk of the infected cells in the brain appear to be of the microglial, macrophage and astrocytes. And without these supporting cells doing their jobs in a normal fashion, it is easy to see how neurons can start dying off.

The severity, characteristics and distribution of HIV-induced injury in the brain varies greatly between affected individuals. It is most likely associated with the viral load (or the number of viral particles) in the brain, which can vary from a few thousand to more than a million copies per mL.

Do HIV-infected people show any signs of the virus entering the brain?

For the majority of people infected with HIV, this entry of the virus into the nervous system is neurologically asymptomatic (meaning they will not notice it), except for the occasional mild headache (for more on this read this review). As a result of the HIV virus entering the brain, however, many infected individuals will suffer from a specific set of neurological disorders, collectively called the AIDS dementia complex (ADC) (also known as HIV-associated cognitive/motor complex, or simply HIV dementia).

So how does HIV infection result in Parkinson’s disease-like features?

As we have suggested in the introduction to this post, on rare occasions (approximately 5% of cases), HIV-infected patients may present an illness virtually identical to Parkinson’s disease. More commonly, people with HIV will exhibit an increased sensitivity to dopamine receptor-blocking agents, such as drugs with a low potential for inducing Parkinsonism, (for example prochlorperazine and metoclopropamide).

The exact mechanism by which HIV infection results in Parkinson’s disease-like features is the subject of debate, but what is clear is that the basal ganglia (a structure involved in Parkinson’s disease) faces the brunt of the HIV infection in the brain. HIV-infected microglia and macrophage are most prominent in the basal ganglia when compared to other brain regions (Click here and here for more on this), and the basal ganglia is where the chemical dopamine from the midbrain is being released.

In addition, there are other changes in the brains of HIV infected people which may aid in the appearance of Parkinsonian features:

 

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Title: Increased frequency of alpha-synuclein in the substantia nigra in human immunodeficiency virusinfection.
Authors: Khanlou N, Moore DJ, Chana G, Cherner M, Lazzaretto D, Dawes S, Grant I, Masliah E, Everall IP; HNRC Group.
Journal: J Neurovirol. 2009 Apr;15(2):131-8.
PMID: 19115126       (This article is OPEN ACCESS if you would like to read it)

The researchers in this study used staining techniques to look at the amount of alpha synuclein – the Parkinson’s associated protein – in slices of brain tissue taken from postmortem autopsies of 73 HIV+ individuals aged between 50 and 76 years of age.

The presence of alpha synuclein in the substantia nigra (an area of the brain affected by Parkinson’s disease) was a lot higher in the HIV+ brains when compared with healthy control samples (16% of the HIV+ brains had high levels of alpha synclein vs 0% for the healthy brains).

Interestingly, nearly all of the brains analysed (35 out of 36 HIV+ brains) had high levels of the Alzheimer’s disease associated protein, beta amyloid (which again raises the question of whether beta amyloid could be playing a defensive role in infections – see our previous post on this). Also interesting, was that there was no correlation between these proteins being present and the age of the person at death – that is to say, older brains did not have more of these proteins when compared with younger brains.

There are also additional ways in which HIV could be causing Parkinson’s-like features, such as:

  • HIV has been shown to affect the protein levels of Parkinson’s disease associated proteins, such as DJ1 and Lrrk2 (Click here and here to read more on this).
  • HIV can, in some cases, increase the level of Dopamine transporter, which would reduce the levels of free floating dopamine in the brain (Click here to read more about this).

How is HIV treated?

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Treating HIV. Source: NPR

There is currently no cure for HIV infection.

There are, however, treatments which help to slow the virus down. These are called Anti-retroviral drugs (HIV is a retrovirus). There are different kinds of anti-retroviral drugs, which act at different stages of the HIV life cycle. Combinations of several anti-retroviral drugs (generally three or four) is known as ‘Highly Active Anti-Retroviral Therapy'(or HAART).

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Mechanism by which four classes of anti-retroviral drugs work against HIV. Source: Wikipedia

As the schematic image above highlights, there are many ways to slow down the HIV virus. For example, you can prevent it from attaching to a cell and fusing with the cell membrane (fusion inhibitors). By treating HIV infected people with multiple medications attacking different parts of the HIV life cycle, the virus has been slowed down.

Does HAART treatments for HIV help with these Parkinson’s-like features?

In some cases, the answer appears to be yes.

There are numerous case studies in the literature which demonstrate the alleviation of HIV-associated Parkinsonian symptoms with HAART, such as this report:

hersh

Title: Parkinsonism as the presenting manifestation of HIV infection: improvement on HAART.
Authors: Hersh BP, Rajendran PR, Battinelli D.
Journal: Neurology. 2001 Jan 23;56(2):278-9.
PMID: 11160977

In this study the researchers described the case of a 37 year old man who developed Parkinson’s like features in the setting of an HIV infection, which were resolved after 1 year of HAART.

Over a period of 4 months, the man developed co-ordination issue, clumsiness and an irregular tremor in his right hand (there was, however, no resting tremor). He noted a generalised slowness and exhibited a tendency towards decreased right arm swinging. He also developed dystonia in the right hand/arm. Following L-dopa treatment (25/100; one tablet 3x per day) there was improvement in balance & co-ordination, speech, facial expression, and the tremor (L-dopa does appear to improve most cases of HIV-associated Parkinson’s-like features).

Six months after first displaying these Parkinsonian features (and two month after initiating L-dopa treatment), the subject was placed on HAART treatment. Four months later, he discontinued L-dopa treatment and 12 months after starting the HAART regime his Parkinsonian features were largely resolved.

More case studies of HAART alleviating HIV-associated Parkinsonisms can be found by clicking here and here.

What does this mean for Parkinson’s disease?

This post was written for the research community rather than people with Parkinson’s disease. I thought the fact that some people with HIV can start to have Parkinson’s like features was an interesting curiosity and wanted to share/spread the information.

Having said that, this post raises some really interesting questions, such as if a virus like HIV can have this effect on the brain, could other viruses be having similar effects? Could some cases of Parkinson’s disease simply be the result of a viral infection? Either multiple hits from a particular virus or different viruses each taking a varying toll over the course of a life time.

This idea would explain many of the curious features of Parkinson’s disease, such as:

  • the asymmetry of the symptoms (people with Parkinson’s usually have the disease starting on one side of the body.
  • the fact that some cells in the brain are more vulnerable to the disease than others (perhaps they are more receptive to a particular virus).
  • the protein clusterings in the cells (Lewy bodies may be defensive efforts against viral infections).

As we have previous mentioned, theories of viral causes for Parkinson’s have been circulating ever since the 1918 flu pandemic (Click here to read our previous post on this topic). About the same time as the influenza virus was causing havoc around the world, another condition began to appear called ‘encephalitis lethargica‘. This disease left many of the victims in a statue-like condition, both motionless and speechless – similar to Parkinson’s disease. Initially, it was assumed that the influenza virus was the causal factor, but more recent research has left us not so sure anymore.

The point is, however, perhaps it is time for us to re-examine the possibility of a viral agent being involved in the development of Parkinson’s disease.

There is new technology that allows us to determine the viral history of each individual from a simple blood test (Click here for more on this), so it would be interesting to compare blood samples from people with Parkinson’s disease with healthy controls to determine any differences.

In addition to the overall question of a viral role in Parkinson’s disease, there also remains the question of why only a small fraction of people with HIV are affected by Parkinsonisms. It could be interesting to genetically screen those people with HIV that exhibit Parkinsonisms and compare them with people with HIV that do not. Do those affected individuals have recognised Parkinson’s related genetic mutations? Or do they have novel genetic variations that could tell us more about Parkinson’s disease?

Food for thought. Would be happy to hear others thoughts.

The banner for today’s post was sourced from AidsServices

George H and Vascular Parkinsonism

~ Simon ~ 10 Comments

george-hw-bush

During Super Bowl 51, ex-president George HW Bush was visibly wheel chair bound. He has in fact been using motorised scooters and wheelchairs since 2012.

His doctors have indicated that he suffers from Vascular Parkinsonism.

In today’s post we will discuss what Vascular Parkinsonism is and how it differs from Parkinson’s disease.

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During a visit to the White house. Source: Heavy

An important concept to understand about the subject matter here:

Parkinsonism is a syndrome, while Parkinson’s is a disease.

A syndrome is a collection of symptoms that characterise a particular condition, while a disease is a pathophysiological response to internal or external factors. The term ‘Parkinsonism’ is an umbrella term that encompasses many conditions which share some of the symptoms of Parkinson’s disease.

There are many different types of Parkinsonism, such as:

  • Idiopathic Parkinson’s disease (the most common type of parkinsonism)
  • Progressive Supranuclear Palsy (PSP)
  • Corticobasal Degeneration (CBD)
  • Multiple System Atrophy (MSA)
  • Essential tremor
  • Vascular Parkinsonism
  • Drug-induced Parkinsonism
  • Dementia with Lewy bodies
  • Inherited Parkinson’s disease
  • Juvenile Parkinson’s disease

All of these conditions fall under the syndrome title of ‘Parkinsonism’, but are all considered distinct/separate diseases in themselves.

So what is Vascular Parkinsonism?

Vascular Parkinsonism was first described in 1929 by Dr Macdonald Critchley (King’s College Hospital, London).

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Macdonald Critchley. Source: Npgprints

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Title: Arteriosclerotic Parkinsonism.
Author: Critchley, M.
Journal: Brain (1929) 52, 23–83
PMID: N/A                                (this article is accessible by clicking here)

It is estimated that approximately 3% to 6% of all cases of Parkinsonism may have a vascular cause. Vascular (or Arteriosclerotic) Parkinsonism is results from a series of small strokes in the basal ganglia area of the brain and can lead to the appearance of symptoms that look like Parkinson’s disease: slow movements, tremors, difficulty walking, and rigidity.

Walking problems are particularly prominent with Vascular Parkinsonism, as the lower half of the body is usually more affected than the upper half. Another sign of Vascular Parkinsonism can be a poor or no response to L-dopa treatment, as production of dopamine is not the problem. Using brain scanning techniques we can see that some people with Vascular Parkinsonism will have a normal Dopamine transporter (DAT) scan – which demonstrates appropriate levels of dopamine being released and reabsorbed in the striatum (the red-white areas in the image below).

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DAT-scan and MR images of 62-y-old male  with Vascular Parkinsonism (A) and 62-y-old male with Parkinson’s disease (B). Source: JNM

The brain scans above are from a person with Vascular Parkinsonism (A) and another person with Parkinson’s disease (B). Firstly, note the reduced levels of red-white areas in the image (B) – this reduction is due to less dopamine is being released and reabsorbed in the striatum in Parkinson’s disease (as there are less dopamine fibres present). Compare that with the relatively normal levels of red-white areas in the image (A), indicating normal levels of dopamine turnover (suggesting dopamine fibres are still present). Next, look at the black and white image in panel (A) and you will see a red arrow pointing at damaged areas (darkened regions) of the striatum – indicative of mini strokes. A dopamine receptor scan may show a reduction in the levels of dopamine receptors as a result of the strokes, meaning that the released dopamine will not be having much effect.

Do we know what can cause the strokes associated with Vascular Parkinsonism?

The symptoms of Vascular Parkinsonism tend to appear suddenly and generally do not progress, unlike Parkinson’s disease. We don’t know for sure what causes the mini strokes associated with Vascular Parkinsonism, and it probably varies from person to person, In general, however, doctors believe that high blood pressure and diabetes are the most likely causal factors (heart disease may also play a role).

What does it all mean?

Some people of Parkinson’s disease may actually have Vascular Parkinsonism, which can result from mini strokes in the basal ganglia region of the brain. They will usually be unresponsive to L-dopa and have more motor issues with their lower half of the body.

While Ex-President George HW Bush’s situation is extremely unfortunate, it reminds us that not all forms of Parkinsonism are Parkinson’s disease – an important factor to keep in mind when considering treatment regimes. We have posted this information here to make the Parkinson’s community more aware of this form of Parkinsonism. Later in the year we will discuss another form of Parkinsonism.

The banner for today’s post was sourced from Ew

PARIS is always a good idea

~ Simon ~ 6 Comments

bzn8qhy

Audrey Hepburn was taking about the city when she uttered the words that title this post, but today we will be talking about the protein that bears the same name: PARIS.

Last week new research was published which demonstrated that in the absence of Parkin and Pink1 protein, the protein PARIS builds up and becomes toxic for cells.

Today’s post will review that research and we’ll discuss what it all means for Parkinson’s disease.

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No label required. A magnificent city. Source: HathawaysofHaworth

Today’s post has nothing to do with the city of Paris, but it is always nice to have photos of this European capital gracing the page.

We have recently discussed the Parkinson’s associated proteins Pink1 and Parkin (click here for that post). Today we will be revisiting these proteins as we discuss another protein that they interact with: PARIS (specifically PARIS1).

What is PARIS?

PARIS (aka TBC1D2 or TBC1 Domain Family Member 2) is a GTPase-activating protein.

What does that mean?

Getting a signal from outside of a cell into the interior is a complicated affair. There are numerous ways to do it, but one of the most common involves ‘G-proteins‘. These are involved with transmitting a signal from the outside of a cell into the interior, and when inside the cell G-proteins act as molecular switches.

G-proteins are located inside the cell membrane and are activated by G-protein-coupled receptors. When a signaling molecule binds to the G-protein-coupled receptor on the outside of the cell membrane, the portion of the receptor inside the cell activates the G-protein which then starts of a chain of events resulting in the signal being passed on.

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Source: Bio1151

The role of GTPase-Activating Proteins in this process is to turn the G protein’s activity off. In step 4 of the image above, a GTPase-Activating Protein (which is not shown) binds to the G-protein and terminate the activity of the signalling event – returning it to an inactive state.

Thus, GTPase-Activating Proteins – like PARIS – are important regulators of signalling inside the cell.

What do we know about PARIS1 in Parkinson’s disease?

So a few years ago, a group of researchers led by Prof Ted Dawson at John Hopkins School of Medicine published this study:

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Title: PARIS (ZNF746) repression of PGC-1α contributes to neurodegeneration in Parkinson’s disease.
Authors: Shin JH, Ko HS, Kang H, Lee Y, Lee YI, Pletinkova O, Troconso JC, Dawson VL, Dawson TM.
Journal: Cell. 2011 Mar 4;144(5):689-702.
PMID: 21376232        (This article is OPEN ACCESS if you would like to read it)

In this study, the researchers noticed that the protein PARIS was accumulating in cells that did not have the Parkinson’s associated protein, Parkin. In those cells, the Parkin gene was mutated so that the Parkin protein was not produced properly. The researchers discovered that Parkin was important for labelling old PARIS protein for disposal. Thus in the absence of Parkin, PARIS protein would not be disposed of and simply piled up.

This build up of PARIS resulted in the loss of dopamine neurons in mice that did not produce Parkin. When the researchers re-introduced normal Parkin protein, the researchers were able to rescue the cell loss. Interestingly, the researchers also found that over production of PARIS in normal mice resulted in cell loss which could be rescued by a similar over production of Parkin.

When they looked in postmortem human brains, the researchers found that levels of PARIS protein were more than two times higher in regions affected by Parkinson’s disease (the striatum and the substantia nigra) of people with sporadic Parkinson’s disease when compared to healthy controls. Interestingly, this increase was only seen with PARIS protein, and not PARIS RNA (where the scientists saw no different with control samples), suggesting a build up of PARIS protein in the Parkinsonian brain.

The investigators concluded that this meant PARIS was could be playing a role in the cell loss associated with Parkinson’s disease.

They followed up this research a few years later with this publication:

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Title: Parkin loss leads to PARIS-dependent declines in mitochondrial mass and respiration.
Authors: Stevens DA, Lee Y, Kang HC, Lee BD, Lee YI, Bower A, Jiang H, Kang SU, Andrabi SA, Dawson VL, Shin JH, Dawson TM.
Journal: Proc Natl Acad Sci U S A. 2015 Sep 15;112(37):11696-701.
PMID: 26324925     (This article is OPEN ACCESS if you would like to read it)

In this study, the same researchers found that when they remove the Parkin protein from the brains of adult mice there would be a decrease in the size and number of mitochondria. We have previous discussed mitochondria – the power stations of the cell – and their loss is bad news for a cell (click here to read more on mitochondria).

The researchers next demonstrated that this loss of mitochondria could reversed by removing PARIS protein from the Parkin mutant mice, and this prevented the loss of dopamine neurons. They also showed that the loss of mitochondria (and loss of dopamine neurons) could be caused by over production of PARIS in normal mice.

These results pointed towards an important role for both Parkin and PARIS in the maintenance of healthy mitochondria.

So what new research has been published about PARIS1?

This study was published last week:

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Title: PINK1 Primes Parkin-Mediated Ubiquitination of PARIS in Dopaminergic Neuronal Survival.
Authors: Lee Y, Stevens DA, Kang SU, Jiang H, Lee YI, Ko HS, Scarffe LA, Umanah GE, Kang H, Ham S, Kam TI, Allen K, Brahmachari S, Kim JW, Neifert S, Yun SP, Fiesel FC, Springer W, Dawson VL, Shin JH, Dawson TM.
Journal: Cell Rep. 2017 Jan 24;18(4):918-932.
PMID: 28122242       (This article is OPEN ACCESS if you would like to read it)

In their study the researchers found that Parkin is not the only Parkinson’s associated protein in the PARIS story.

We have previously talked about the protein Pink1 (click here to read more on) – and yes, you would be forgiven if you start to think that all Parkinson’s related proteins start with the latter ‘P’. Pink1 grabs Parkin and causes it to bind to dysfunctional mitochondria. Parkin then signals to the rest of the cell for that particular mitochondria to be disposed of. In this study, the researchers found that Pink1 also grabs PARIS and signals for Parkin to dispose of it. In the absence of Pink1, normal Parkin protein does not label old PARIS protein for disposal and PARIS starts to pile up.

The researchers then began manipulating the levels of Pink in the brains of mice and they observed PARIS-dependent cell loss – that is to say, in the absence of Pink1, cells died only when PARIS was present.

These findings suggest that therapies targeting PARIS could be used in people with Parkinson’s disease who are carrying either a Parkin or a Pink1 mutation (both very common in early onset Parkinson’s disease).

What does it all mean?

People with early onset Parkinson’s disease quite often have a genetic mutation in one of a small number of genes – Pink1 and Parkin being prominent amongst these genes. The researchers who conducted the study that we have reviewed today have identified a common mechanism by which both of these proteins could be acting in their roles in Parkinson’s disease: a protein called PARIS.

Currently there is no treatment (that we are aware of) that targets the PARIS protein – nothing in the clinic nor being experimentally tested. Obviously, however, PARIS represents a VERY interesting protein for further investigations. The Dawson lab has several patents on PARIS (Click here and here for more on these), so evidently people will be working on drug candidates that inhibit PARIS.

There is a naturally occurring inhibitor, a micro RNA cluster miR-17-92 (also known as oncomir-1), which reduces the production of PARIS protein by blocking PARIS RNA (Click here for more on this). Using this micro RNA to target PARIS will be very difficult (both activating/delivering the micro RNA and unknown off target effects).

We are assuming that Prof Dawson and colleagues are rapidly screening compounds to determine which can block or inhibit PARIS activity and we will eagerly wait to see the results of that work.

Watch this space.

The banner for today’s post was sourced from Wallpapercave

EDITORIAL NOTE: Yay, 100 posts!

Something ‘new and fresh’ from Korea

~ Simon ~ 3 Comments

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The word ‘Kainos‘ comes from ancient Greek, meaning ‘new’ or ‘fresh’.

A company in South Korea has chosen to use this word as their name.

Why?

In today’s post we will discuss a clinical trial that started this week that is taking a ‘new and fresh’ approach to treating Parkinson’s disease.

south_korea

Enchanting country. Source: Eoasia

South Korea is an amazing place, with a long and proud history of innovation and technological development. This week a biotech company there called Kainos Medicine has added itself to that history by initiating a clinical trial that takes a new approach to treating Parkinson’s disease.

As Kainos Medicine points out on their website, the current treatment options for Parkinson’s disease function by alleviating symptoms, for example L-dopa simply replaces the lost dopamine rather than treating the underlying disease. Kainos’s new experimental treatment, called KM-819, is trying to help in a different way: it is trying to slow down the cell death that is associated with Parkinson’s.

How does it do that?

KM-819 is an inhibitor of Fas Associated Factor 1 (or FAF1).

And what is FAF1?

Fas Associated Factor 1 is a protein that interacts with and enhances the activity of a protein on the surface of cells with the ominous name: Fas Cell Surface Death Receptor…and yes, the use of the word ‘death’ in that name should give you some indication as to the function of this protein. When Fas Cell Surface Death Receptor gets activated on any given cell, things have definitely taken a turn for the worse for that particular cell.

Fas Cell Surface Death Receptor (also called CD95) is an initiator of apoptosis.

3-s2-0-b9780323069472100203-f20-05-9780323069472

FasSource: Sciencedirect

What is apoptosis?

Apoptosis (from Ancient Greek for “falling off”) is the process of programmed cell death – a cell initiates a sequence of events that result in the cell shutting down and dying.

apoptosis_b

The process of apoptosis. Source: Abnova

Apoptosis is a very clean and organise process of a cell being removed from the body, with it eventually being broken down into small units (called apoptotic bodies) which are consumed by other cells.

Sounds interesting, but what research has been done on FAF1 and Parkinson’s disease?

Back in 2008, this research report was published:

faf1

Title: Fas-associated factor 1 and Parkinson’s disease.
Authors: Betarbet R, Anderson LR, Gearing M, Hodges TR, Fritz JJ, Lah JJ, Levey AI.
Journal: Neurobiol Dis. 2008 Sep;31(3):309-15.
PMID: 18573343   (This article is OPEN ACCESS if you would like to read it)

The researcher who conducted this study noticed that the FAF1 gene was located in the ‘PARK 10’ region of chromosome 1. PARK regions are areas of our DNA where mutations (or disruptions to the sequence of DNA) can result in increased vulnerability to Parkinson’s disease (there are currently at least 20 PARK regions). PARK 10 is a region of DNA in which mutations have been associated with late-onset Parkinson’s disease. The scientists thought this was interesting and investigated FAF1 in the context of Parkinson’s disease.

When they looked at postmortem brains, the researchers found that FAF1 levels were significantly increased in brains from people with Parkinson’s disease when compared to brains from healthy control cases. In addition, increased levels of FAF1 exaggerated the cell death observed in different cell culture models of Parkinson’s disease, suggesting an important role for FAF1 in sporadic Parkinson’s disease.

NOTE: More recently, a closer analysis of the PARK10 region resulted in a shrinking of the area which resulted in FAF1 falling outside the PARK10 domain (click here and here to see that research). We are currently not sure if genetic variations in the FAF1 gene infer vulnerability to PD.

This initial work led others to researching FAF1 in the context of Parkinson’s disease and in 2013 this research report was published:

faf2

Title: Accumulation of the parkin substrate, FAF1, plays a key role in the dopaminergic neurodegeneration.
Authors: Sul JW, Park MY, Shin J, Kim YR, Yoo SE, Kong YY, Kwon KS, Lee YH, Kim E.
Journal: Hum Mol Genet. 2013 Apr 15;22(8):1558-73.
PMID: 23307929

These researchers found that Parkinson’s associated protein, Parkin (which we have briefly discussed in a previous post) labels FAF1 for disposal. And they found in the absence of Parkin there was a build up of FAF1, making the cells more vulnerable to apoptosis. They followed this finding up by demonstrating that FAF1-mediated cell death was rescued by re-introducing the normal parkin protein. Interestingly, there was no rescue when the mutant parkin protein was re-introduced. These results suggest that normal Parkin acts as an inhibitor FAF1.

To further investigate this finding, the researchers next modelled Parkinson’s disease in genetically engineered mice which had the FAF1 gene removed. They found that the behaviour motor problems and loss of dopamine cells in the brain was significantly reduced in the FAF1 mutant mice, indicating that the FAF1 pathway could be a worthy target for future Parkinson’s disease treatment.

And this and other research has led those same researchers to the clinical trial started in Korea by Kainos Medicine.

So what is the clinical trial all about?

The company will be conducting a phase 1 dose-escalation clinical trial in South Korea, which will evaluate the safety, tolerability, and biochemical properties of their drug KM-819 in 48 healthy adults (click here to read more about the trial).

This is the very first step in the clinical trial process.

The study is split in two parts: Part A is a single dose of KM-819 or a placebo given in ascending doses to participants. And Part B is the same except that multiple ascending doses of the compound will be given to the participants.

The trial will last around six weeks, and – according to the press release – the first subject has just been dosed.

What does it all mean?

Parkinson’s disease is a neurodegenerative condition, which means that certain cells in the brain are dying. Medication that could block that cell death from occurring represents an interesting way of treating the disease and this is what Kainos are attempting to do.

Blocking or slowing cell death is a tricky business, however, because in other parts of the body, cell death is a very necessary biological process. In some areas of our body, cells are born, conduct a particular function and die off relatively quickly. By slowing that cell death in the brain which may be a good thing, we may be causing issues elsewhere in the body, which would be bad.

In addition there has recently been concerns raised about the clinical use of apoptosis inhibitors, such as this study:

liver

Title: Caspase Inhibition Prevents Tumor Necrosis Factor-α-Induced Apoptosis and Promotes Necrotic CellDeath in Mouse Hepatocytes in Vivo and in Vitro.
Authors: Ni HM, McGill MR, Chao X, Woolbright BL, Jaeschke H, Ding WX.
Journal: Am J Pathol. 2016 Oct;186(10):2623-36.
PMID: 27616656

The researchers who conducted this study found that using apoptosis inhibitors on a mouse model of liver disease did stop apoptosis from occurring, but this didn’t save the cells which eventually died via another cell death mechanism called necrosis (from the Greek meaning “death, the act of killing” – lots of Greek in this post!). In necrosis, rather than breaking down in a systematic and organised fashion (apoptosis), a cell will simply rupture and fall apart. Very messy.

Thus there is the possibility with the Kainos drug, KM-819, will protect cells in the Parkinsonian brain from dying via apoptosis, but as the disease continues to progress those cells may become more ill and eventually disappear as a result of necrosis. That said, if the drug can slow down Parkinson’s disease, it would still represent a major step forward in our treatment of the condition!

The connection with Parkin is also very interesting.

It would be wise for future phase 2 and 3 trials – which will test efficacy – to include (or specifically recruit) people with Parkinson’s disease who have mutations in the Parkin gene. This is a very small proportion of the overall Parkinson’s community (approx. 20% of people with early onset PD have a Parkin mutation – click here to read more on this), but if the drug is going to be effective, these would be the best people to initially test it in.

This will be a very interesting set of clinical trials to watch. The phase 1 safety trial will be very quick (6 weeks), and hopefully Kainos Medicine will be able to progress rapidly to a phase 2 efficacy trial. Fingers crossed for positive results.

The banner for today’s post was sourced from Koreabizwire