An Advanced Glycation Endproduct (or AGE) is a protein or lipid that has become glycated.
Glycation is a haphazard process that impairs the normal functioning of molecules. It occurs as a result of exposure to high amounts of sugar. These AGEs are present at above average levels in people with diabetes and various ageing-related disorders, including neurodegenerative conditions. AGEs have been shown to trigger signalling pathways within cells that are associated with both oxidative stress and inflammation, but also cell death.
RAGE (or receptor of AGEs) is a molecule in a cell membrane that becomes activated when it interacts with various AGEs. And this interaction mediates AGE-associated toxicity issues. Recently researchers found that that neurons carrying the Parkinson’s associated LRRK2 G2019S genetic variant are more sensitive to AGEs than neurons without the genetic variant.
In today’s post we will look at what AGE and RAGE are, review the new LRRK2 research, and discuss how blocking RAGE could represent a future therapeutic approach for treating Parkinson’s.
The wonder of ageing. Source: Club-cleo
NOTE: Be warned, the reading of this post may get a bit confusing. We are going to be discussing ageing (as in the body getting old) as well as AGEing (the haphazard process processing of glycation). For better clarification, lower caps ‘age’ will refer to getting old, while capitalised ‘AGE’ will deal with that glycation process. I hope this helps.
Ageing means different things to different people.
For some people ageing means more years to add to your life and less activity. For others it means more medication and less hair. More wrinkles and less independence; more arthritis and less dignity; More candles, and less respect from that unruly younger generation; More… what’s that word I’m thinking of? (forgetfulness)… and what were we actually talking about?
Wisdom is supposed to come with age, but as comedian/entertainer George Carlin once said “Age is a hell of a price to pay for wisdom”. I have to say though, that if I ever meet Mr Carlin, I would suggest to him that I’m feeling rather ripped off!
George Carlin. Source: Thethornycroftdiatribe
Whether we like it or not, from the moment you are born, ageing is an inevitable part of our life. But this has not stopped some adventurous scientific souls from trying to understand the process, and even try to alter it in an attempt to help humans live longer.
Regardless of whether you agree with the idea of humans living longer than their specified use-by-date, some of this ageing-related research could have tremendous benefits for neurodegenerative conditions, like Parkinson’s.
What do we know about the biology of ageing?
For a long time researchers have lacked truly disease-relevant models of Parkinson’s.
We have loaded cells with toxins to cause cell death, we have loaded cells with mutant proteins to cause cell death, we have loaded cells with… well, you get the idea. Long story short though, we have never had proper models of Parkinson’s – that is a model which present all of the cardinal features of the condition (Lewy bodies, cell loss, and motor impairment).
The various models we have available have provided us with a wealth of knowledge about the biology of how cells die and how we can protect them, which has led to numerous experimental drugs being tested in the clinic. But there has always been a linger question of ‘how disease-relevant are these models?’
This situation may be about to change.
In today’s post we will look at new research in which Japanese researchers have genetically engineered mice in which they observed the generation of Lewy bodies, the loss of dopamine neurons and motor impairments. We will look at how these mice have been generated, and what it may tell us about Parkinson’s.
Walt Disney. Source: PBS
Ok, before we start today’s post: Five interesting facts about the animator Walt Disney (1901 – 1966):
- Disney dropped out of high school at age 16 with the goal of joining the Army to help out in the war effort. He was rejected for being underage, but was able to get a job as an ambulance driver with the Red Cross in France.
- From 1928 (the birth of Mickey Mouse) until 1947, Disney himself performed the voice of Mickey.
- Mickey Mouse was originally named “Mortimer Mouse”, but it was Disney’s wife who suggested that the name Mortimer sounded too pompous (seriously, can you imagine a world with the “Mortimer Mouse show”?). She convinced Disney to change the name to Mickey (the name Mortimer was later given to one of Mickey’s rivals).
- To this day, Disney holds the record for the most individual Academy Awards and nominations. Between 1932 and 1969, he won 22 Academy Awards and was nominated 59 times (Source).
- And best of all: On his deathbed as he lay dying from lung cancer, Disney wrote the name “Kurt Russell” on a piece of paper. They were in effect his ‘last words’. But no one knows what they mean. Even Kurt is a bit perplexed by it all. He (along with many others) was a child actor contracted to the Disney company at the time, but why did Walt write Russell’s name as opposed to something more deep and meaningful (no disrespect intended towards Mr Russell).
Actor Kurt Russell. Source: Fxguide
When asked why he thought his great creation “Mickey mouse” was so popular, Walt Disney responded that “When people laugh at Mickey Mouse, it’s because he’s so human; and that is the secret of his popularity”.
Mickey Mouse. Source: Ohmy.Disney
This is a curious statement.
Curious because in biomedical research, mice are used in experiments to better understand the molecular pathways underlying basic biology and for the testing of novel therapeutics, and yet they are so NOT human.
There are major biological differences between us and them.
Not human. Source: USNews
It has been a major dilemma for the research community for some time with regards to translating novel therapies to humans, and it raises obvious ethical questions of whether we should be using mice at all for the basic research if they are so different from us. This problem is particularly apparent in the field of immunology, where the differences between ‘mice and men’ is so vast in some cases that researcher have called for moving away from mice entirely and focusing on solely human models (Click here and here for a good reads on this topic).
What does this have to do with Parkinson’s?
Last year at the Intel International Science and Engineering Fair, a young high school student named Jeremiah Pate (Image above) took first Place in his category and third prize overall in the Dudley R. Herschbach Stockholm International Youth Science Seminar Award.
This competition involved nearly seven million high school students from all over the world. And by being a winner in the competition, Jeremiah received an all expenses paid trip to attend the Nobel Prize Awards in Stockholm Sweden.
Jeremiah’s award winning project was about his efforts to find a possible cure for Parkinson’s.
In today’s post we will look at the interesting story of how Jeremiah became interested in Parkinson’s and discuss why impatience is a virtue.
We all like stories that involve something bold.
The moon-shot. The last stand against impossible odds. The underrated boxer beating the champ. The enthusiasts putting Gossamer satellites into space. Big-obstacle-being-overcome, that sort of stuff.
I personally really like those stories about individuals with a very specific goal and the determination to let nothing stand between them and achieving it. Those folks who are not satisfied with the status quo and want to change things for the better. Here at the SoPD, we have previously tried to highlight individuals like this within the Parkinson’s research community (for example, Dr Lysimachos Zografos and Sara (soon to be Dr) Riggare). And in keeping with that tradition, today’s post is about a similar individual.
His name is Jeremiah.
And the story begins at the First Baptist Church in Mammoth, Arizona.
The great ice hockey player Wayne Gretzky once said “A good hockey player plays where the puck is. A great hockey player plays where the puck is going to be” (the original quote actually came from his father, Walter).
At the start of each year, it is a useful practise to layout what is planned for the next 12 months. This can help us better anticipate where ‘the puck’ will be, and allow us to prepare for things further ahead.
2017 was an incredible year for Parkinson’s research, and there is a lot already in place to suggest that 2018 is going to be just as good (if not better).
In this post, we will lay out what we can expect over the next 12 months with regards to the Parkinson’s-related clinical trials research of new therapies.
Charlie Munger (left) and Warren Buffett. Source: Youtube
Many readers will be familiar with the name Warren Buffett.
The charming, folksy “Oracle of Omaha” is one of the wealthiest men in the world. And he is well known for his witticisms about investing, business and life in general.
Warren Buffett. Source: Quickmeme
He regularly provides great one liners like:
“We look for three things [in good business leaders]: intelligence, energy, and integrity. If they don’t have the latter, then you should hope they don’t have the first two either. If someone doesn’t have integrity, then you want them to be dumb and lazy”
“Work for an organisation of people you admire, because it will turn you on. I always worry about people who say, ‘I’m going to do this for ten years; and if I really don’t like it very much, then I’ll do something else….’ That’s a little like saving up sex for your old age. Not a very good idea”
“Choosing your heroes is very important. Associate well, marry up and hope you find someone who doesn’t mind marrying down. It was a huge help to me”
Mr Buffett is wise and a very likeable chap.
Few people, however, are familiar with his business partner, Charlie Munger. And Charlie is my favourite of the pair.
In Silicon valley (California), everyone is always looking for the “next killer app” – the piece of software (or application) that is going to change the world. The revolutionary next step that will solve all of our problems.
The title of today’s post is a play on the words ‘killer app’, but the ‘app’ part doesn’t refer to the word application. Rather it relates to the Alzheimer’s disease-related protein Amyloid Precursor Protein (or APP). Recently new research has been published suggesting that APP is interacting with a Parkinson’s disease-related protein called Leucine-rich repeat kinase 2 (or LRRK2).
The outcome of that interaction can have negative consequences though.
In today’s post we will discuss what is known about both proteins, what the new research suggests and what it could mean for Parkinson’s disease.
Seattle. Source: Thousandwonders
In the mid 1980’s James Leverenz and Mark Sumi of the University of Washington School of Medicine (Seattle) made a curious observation.
After noting the high number of people with Alzheimer’s disease that often displayed some of the clinical features of Parkinson’s disease, they decided to examined the postmortem brains of 40 people who had passed away with pathologically confirmed Alzheimer’s disease – that is, an analysis of their brains confirmed that they had Alzheimer’s.
What the two researchers found shocked them:
Title: Parkinson’s disease in patients with Alzheimer’s disease.
Authors: Leverenz J, Sumi SM.
Journal: Arch Neurol. 1986 Jul;43(7):662-4.
Of the 40 Alzheimer’s disease brains that they looked at nearly half of them (18 cases) had either dopamine cell loss or Lewy bodies – the characteristic features of Parkinsonian brain – in a region called the substantia nigra (where the dopamine neurons are located). They next went back and reviewed the clinical records of these cases and found that rigidity, with or without tremor, had been reported in 13 of those patients. According to their analysis 11 of those patients had the pathologic changes that warranted a diagnosis of Parkinson’s disease.
And the most surprising aspect of this research report: Almost all of the follow up studies, conducted by independent investigators found exactly the same thing!
It is now generally agreed by neuropathologists (the folks who analyse sections of brain for a living) that 20% to 50% of cases of Alzheimer’s disease have the characteristic round, cellular inclusions that we call Lewy bodies which are typically associated with Parkinson disease. In fact, in one analysis of 145 Alzheimer’s brains, 88 (that is 60%!) had chemically verified Lewy bodies (Click here to read more about that study).
A lewy body (brown with a black arrow) inside a cell. Source: Cure Dementia
Oh, and if you are wondering whether this is just a one way street, the answer is “No sir, this phenomenon works both ways”: the features of the Alzheimer’s brain (such as the clustering of a protein called beta-amyloid) are also found in many cases of pathologically confirmed Parkinson’s disease (Click here and here to read more about this).
So what are you saying? Alzheimer’s and Parkinson’s disease are the same thing???
The clustering of a protein called alpha synuclein is one of the cardinal features of the brain of a person with Parkinson’s disease.
Recently published research has demonstrated that tiny antibodies (called nanobodies) derived from llamas (yes, llamas) are very effective at reducing this clustering of alpha synuclein in cell culture models of Parkinson’s disease.
In today’s post, we will discuss the science, review the research and consider what it could all mean for Parkinson’s disease.
Llama. Source: Imagesanimals
Ok, I confess: This post has been partly written purely because I really like llamas. And I’m not ashamed to admit it either.
I mean, look at them! They are fantastic:
Very cute. But what does this have to do with Parkinson’s disease?
Indeed. Let’s get down to business.
This post has also been written because llamas have a very interesting biological characteristic that is now being exploited in many areas of medical research, including for Parkinson’s disease.
On the 27th June, 1997, a research report was published in the prestigious scientific journal ‘Science’ that would change the world of Parkinson’s disease research forever.
And I am not exaggerating here.
The discovery that genetic variations in a gene called alpha synuclein could increase the risk of developing Parkinson’s disease opened up whole new areas of research and eventually led to ongoing clinical trials of potential therapeutic applications.
Todays post recounts the events surrounding the discovery, what has happened since, and we will discuss where things are heading in the future.
It is fair to say that 1997 was an eventful year.
In world events, President Bill Clinton was entering his second term, Madeleine Albright became the first female Secretary of State for the USA, Tony Blair became the prime minister of the UK, and Great Britain handed back Hong Kong to China.
#42 – Bill Clinton. Source: Wikipedia
In the world of entertainment, author J. K. Rowling’s debut novel “Harry Potter and the Philosopher’s Stone” was published by Bloomsbury, and Teletubbies, South Park, Ally McBeal, and Cold Feet (it’s a British thing) all appeared on TV for the first time, amusing and entertaining the various age groups associated with them.
South Park. Source: Hollywoodreporter
Musically, rock band Blur released their popular hit song ‘Song 2‘ (released 7th April), “Bitter Sweet Symphony” by the Verve entered the UK charts at number 2 in June, and rapper Notorious B.I.G. was killed in a drive by shooting. Oh, and let’s not forget that “Tubthumping” (also known as “I Get Knocked Down”) by Chumbawamba was driving everybody nuts for its ubiquitous presence.
And at the cinemas, no one seemed to care about anything except a silly movie called Titanic.
Titanic. Source: Hotspot
Feeling old yet?
Please excuse our use of UK slang in the title of this post, but a group of Australian researchers have recently discovered something really interesting about Parkinson’s disease.
And being a patriotic kiwi, it takes something REALLY interesting for me to even acknowledge that other South Pacific nation. This new finding, however, could be big.
In today’s post, we will review new research dealing with a protein called SOD1, and discuss what it could mean for the Parkinson’s community.
The number of dark pigmented dopamine cells in the substantia nigra are reduced in the Parkinson’s disease brain (right). Source: Adaptd from Memorangapp
Every Parkinson’s-associated website and every Parkinson’s disease researchers will tell you exactly the same thing when describing the two cardinal features in the brain of a person who died with Parkinson’s disease:
- The loss of certain types of cells (such as the dopamine producing cells of the substantia nigra region of the brain – see the image above)
- The clustering (or aggregation) of a protein called Alpha synuclein in tightly packed, circular deposits, called Lewy bodies (see image below).
A Lewy body inside a cell. Source: Adapted from Neuropathology-web
The clustered alpha synuclein protein, however, is not limited to just the Lewy bodies. In the affected areas of the brain, aggregated alpha synuclein can be seen in the branches of cells – see the image below where alpha synuclein has been stained brown on a section of brain from a person with Parkinson’s disease.
Examples of Lewy neurites (indicated by arrows). Source: Wikimedia
Now, one of the problems with our understanding of Parkinson’s disease is disparity between the widespread presence of clustered alpha synuclein and very selective pattern of cell loss. Alpha synuclein aggregation can be seen distributed widely around the affected areas of the brain, but the cell loss will be limited to specific populations of cells.
If the disease is killing a particular population of cells, why is alpha synuclein clustering so wide spread?
So why is there a difference?
We don’t know.
It could be that the cells that die have a lower threshold for alpha synuclein toxicity (we discussed this is a previous post – click here?).
But this question regarding the difference between these two features has left many researchers wondering if there may be some other protein or agent that is actually killing off the cells and then disappearing quickly, leaving poor old alpha synuclein looking rather guilty.
Poor little Mr “A Synuclein” got the blame, but his older brother actually did it! Source: Youtube
And this is a very serious discussion point.
This year of 2017 represents the 200th anniversary of James Parkinson’s first description of Parkinson’s disease, but it also represents the 20th anniversary since the association between alpha synuclein and PD was first established. We have produced almost 7,000 research reports on the topic of alpha synuclein and PD during that time, and we currently have ongoing clinical trials targetting alpha synuclein.
But what if our basic premise – that alpha synuclein is the bad guy – is actually wrong?
Is there any evidence to suggest this?
We are just speculating here, but yes there is.
For example, in a study of 904 brains, alpha synuclein deposits were observed in 11.3% of the brains (or 106 cases), but of those cases only 32 had been diagnosed with a neurodegenerative disorder (Click here to read more on this). The remaining 74 cases had demonstrated none of the clinical features of Parkinson’s disease.
So what else could be causing the cell death?
Well, this week some scientists from sunny Sydney (Australia) reported a protein that could fit the bill.
Sydney. Source: Vagabond
The interesting part of their finding is that the protein is also associated with another neurodegenerative condition: Amyotrophic lateral sclerosis.
Remind me again, what is Amyotrophic lateral sclerosis?
Parkinson’s disease and Amyotrophic lateral sclerosis (ALS) are the second and third most common adult-onset neurodegenerative conditions (respectively) after Alzheimer’s disease. We recently discussed ALS in a previous post (Click here to read that post).
ALS, also known as Lou Gehrig’s disease and motor neuron disease, is a neurodegenerative condition in which the neurons that control voluntary muscle movement die. The condition affects 2 people in every 100,000 each year, and those individuals have an average survival time of two to four years.
You may have heard of ALS due to it’s association with the internet ‘Ice bucket challenge‘ craze that went viral in 2014-15.
The Ice bucket challenge. Source: Forbes
What is the protein associated with ALS?
In 1993, scientists discovered that mutations in the gene called SOD1 were associated with familial forms of ALS (Click here to read more about this). We now know that mutations in the SOD1 gene are associated with around 20% of familial cases of ALS and 5% of sporadic ALS.
The SOD1 gene produces an enzyme called Cu-Zn superoxide dismutase.
This enzyme is a very powerful antioxidant that protects the body from damage caused by toxic free radical generated in the mitochondria.
SOD1 protein structure. Source: Wikipedia
One important note here regarding ALS: the genetic mutations in the SOD1 gene do not cause ALS by affecting SOD1’s antioxidant properties (Click here to read more about this). Rather, researchers believe that the cell death seen in SOD1-associated forms of ALS is the consequences of some kind of toxic effect caused by the mutant protein.
So what did the Aussie researchers find about SOD1 in Parkinson’s disease?
This week, the Aussie researchers published this research report:
Title: Amyotrophic lateral sclerosis-like superoxide dismutase 1 proteinopathy is associated withneuronal loss in Parkinson’s disease brain.
Authors: Trist BG, Davies KM, Cottam V, Genoud S, Ortega R, Roudeau S, Carmona A, De Silva K, Wasinger V, Lewis SJG, Sachdev P, Smith B, Troakes C, Vance C, Shaw C, Al-Sarraj S, Ball HJ, Halliday GM, Hare DJ, Double KL.
Journal: Acta Neuropathol. 2017 May 19. doi: 10.1007/s00401-017-1726-6.
Given that oxidative stress is a major feature of Parkinson’s disease, the Aussie researchers wanted to investigate the role of the anti-oxidant enzyme, SOD1 in this condition. And what they found surprised them.
Heck, it surprised us!
Two areas affected by Parkinson’s disease – the substantia nigra (where the dopamine neurons reside; SNc in the image below) and the locus coeruleus (an area in the brain stem that is involved with physiological responses to stress; LC in the image below) – exhibited little or no SOD1 protein in the control brains.
But in the Parkinsonian brains, there was a great deal of SOD1 protein (see image below).
SO1 staining in PD brain and Control brains. Source: Springer
In the image above, you can see yellowish-brown stained patches in both the PD and control images. This a chemical called neuromelanin and it can be used to identify the dopamine-producing cells in the SNc and LC. The grey staining in the PD images (top) are cells that contain SOD1. Note the lack of SOD1 (grey staining) in the control images (bottom).
Approximately 90% of Lewy bodies in the Parkinson’s affected brains contained SOD1 protein. The investigators did report that the levels of SOD1 protein varied between Lewy bodies. But the clustered (or ‘aggregated’) SOD1 protein was not just present with alpha synuclein, often it was found by itself in the degenerating regions.
The researchers occasional saw SOD1 aggregation in regions of age-matched control brains, and they concluded that a very low level of SOD1 must be inherent to the normal ageing process.
But the density of SOD1 clustering was (on average) 8x higher in the SNc and 4x higher in the LC in the Parkinsonian brain compared to age-matched controls. In addition, the SOD1 clustering was significantly greater in these regions than all of the non-degenerating regions of the same Parkinson’s disease brains.
The investigators concluded that these data suggest an association between SOD1 aggregation and neuronal loss in Parkinson’s disease. Importantly, the presence of SOD1 aggregations “closely reflected the regional pattern of neuronal loss”.
They also demonstrated that the SOD1 protein in the Parkinsonian brain was not folded correctly, a similar characteristic to alpha synuclein. A protein must fold properly to be able to do it’s assigned jobs. By not folding into the correct configuration, the SOD1 protein could not do it’s various functions – and the investigators observed a 66% reduction in SOD1 specific activity in the SNc of the Parkinson’s disease brains.
Interestingly, when the researchers looked at the SNc and LC of brains from people with ALS, they identified SOD1 aggregates matching the SOD1 clusters they had seen in these regions of the Parkinson’s disease brain.
Is this the first time SOD1 has been associated with Parkinson’s disease?
No, but it is the first major analysis of postmortem Parkinsonian brains. SOD1 protein in Lewy bodies has been reported before:
Title: Cu/Zn superoxide dismutase-like immunoreactivity is present in Lewy bodies from Parkinson disease: a light and electron microscopic immunocytochemical study
Authors: Nishiyama K, Murayama S, Shimizu J, Ohya Y, Kwak S, Asayama K, Kanazawa I.
Journal: Acta Neuropathol. 1995;89(6):471-4.
The investigators behind this study reported SOD1 protein was present in Lewy bodies, in the substantia nigra and locus coeruleus of brains from five people with Parkinson’s disease. Interestingly, they showed that SOD1 is present in the periphery of the Lewy body, similar to alpha synuclein. Both of these protein are present on the outside of the Lewy body, as opposed to another Parkinson’s associated protein, Ubiquitin, which is mainly present in the centre (or the core) of Lewy bodies (see image below).
A more recent study also demonstrated SOD1 protein in the Parkinsonian brain, including direct interaction between SOD1 and alpha synuclein:
Title: α-synuclein interacts with SOD1 and promotes its oligomerization
Authors: Helferich AM, Ruf WP, Grozdanov V, Freischmidt A, Feiler MS, Zondler L, Ludolph AC, McLean PJ, Weishaupt JH, Danzer KM.
Journal: Mol Neurodegener. 2015 Dec 8;10:66.
PMID: 26643113 (This article is OPEN ACCESS if you would like to read it)
These researchers found that alpha synuclein and SOD1 interact directly, and they noted that Parkinson’s disease related mutations in alpha synuclein (A30P, A53T) and ALS associated mutation in SOD1 (G85R, G93A) modify the binding of the two proteins to each other. They also reported that alpha synuclein accelerates SOD1 aggregation in cell culture. This same group of researchers published another research report last year in which they noted that aggregated alpha synuclein increases SOD1 clustering in a mouse model of ALS (Click here for more on this).
Are there any genetic mutations in the SOD1 gene that are associated with Parkinson’s disease?
Two studies have addressed this question:
Title: Sequence of the superoxide dismutase 1 (SOD 1) gene in familial Parkinson’s disease.
Authors: Bandmann O, Davis MB, Marsden CD, Harding AE.
Journal: J Neurol Neurosurg Psychiatry. 1995 Jul;59(1):90-1.
PMID: 7608718 (This article is OPEN ACCESS if you would like to read it)
And then in 2001, a second analysis:
Title: Genetic polymorphisms of superoxide dismutase in Parkinson’s disease.
Authors: Farin FM, Hitosis Y, Hallagan SE, Kushleika J, Woods JS, Janssen PS, Smith-Weller T, Franklin GM, Swanson PD, Checkoway H.
Journal: Mov Disord. 2001 Jul;16(4):705-7.
Both studies found no genetic variations in the SOD1 gene that were more frequent in the Parkinson’s affected community than the general population. So, no, there are no SOD1 genetic mutations that are associated with Parkinson’s disease.
Are there any treatments targeting SOD1 that could be tested in Parkinson’s disease?
Great question. Yes there are. And they have already been tested in models of PD:
Title: The hypoxia imaging agent CuII(atsm) is neuroprotective and improves motor and cognitive functions in multiple animal models of Parkinson’s disease.
Authors: Hung LW, Villemagne VL, Cheng L, Sherratt NA, Ayton S, White AR, Crouch PJ, Lim S, Leong SL, Wilkins S, George J, Roberts BR, Pham CL, Liu X, Chiu FC, Shackleford DM, Powell AK, Masters CL, Bush AI, O’Keefe G, Culvenor JG, Cappai R, Cherny RA, Donnelly PS, Hill AF, Finkelstein DI, Barnham KJ.
Title: J Exp Med. 2012 Apr 9;209(4):837-54.
PMID: 22473957 (This article is OPEN ACCESS if you would like to read it)
CuII(atsm) is a drug that is currently under clinical investigation as a brain imaging agent for detecting hypoxia (damage caused by lack of oxygen – Click here to read more about this).
The researchers conducting this study, however, were interested in this compound for other reasons: CuII(atsm) is also a highly effective scavenger of a chemical called ONOO, which can be very toxic. CuII(atsm) not only inhibits this toxicity, but it also blocks the clustering of alpha synuclein. And given that CuII(atsm) is capable of crossing the blood–brain barrier, these investigators wanted to assess the drug for its ability to rescue model of Parkinson’s disease.
And guess what? It did!
And not just in one model of Parkinson’s disease, but FOUR!
The investigators even waited three days after giving the neurotoxins to the mice before giving the CuII(atsm) drug, and it still demonstrated neuroprotection. It also improved the behavioural features of these models of Parkinson’s disease.
Is CuII(atsm) being tested for anything else in Clinical trials?
Yes, there is a clinical trial ongoing for ALS in Australia.
The Phase I study, being run by Collaborative Medicinal Development Pty Limited, is a dose escalating study of Cu(II)ATSM to determine if this drug is safe for use in ALS (Click here for more on this study).
Cu(II)ATSM is an orally administered drug that inhibits the activity of misfolded SOD1 protein. It has been shown to paradoxically increase mutant SOD1 protein in a mouse model of ALS, but it also provides neuroprotection and improves the outcome for these mice (Click here to read more on this).
If this trial is successful, it would be interesting to test this drug on a cohort of people with Parkinson’s disease. Determining which subgroup of the Parkinson’s affected community would most benefit from this treatment is still to be determined. There is some evidence published last year that suggests people with genetic mutations in the Parkinson’s associated gene PARK2 could benefit from the approach (Click here to read more on this). More research, however, is needed in this area.
So what does it all mean?
Right, so summing up, a group of Australian researchers have reported that the ALS associated protein SOD1 is closely associated with the cell death that we observe in the brains of people with Parkinson’s disease.
They suggest that this could highlight a common mechanisms of toxic SOD1 aggregation in both Parkinson’s disease and ALS. Individuals within the Parkinson’s affected community do not appear to have any genetic mutations in the SOD1 gene, which makes this finding is very interesting.
What remains to be determined is whether SOD1 aggregation is a “primary pathological event”, or if it is secondary to some other disease causing agent. We are also waiting to see if a clinical trial targeting SOD1 in ALS is successful. If it is, there may be good reasons for targeting SOD1 as a novel treatment for Parkinson’s disease.
The banner for today’s post was sourced from Pinterest
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.
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).
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).
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).
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:
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.
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:
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.
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?
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.
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:
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.
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?
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.
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]
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.
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
The great American baseball legend, Yogi Berra, once said: “In theory, there is no difference between theory and practice. But in practice, there is.”
Silly as it reads, there is a great deal of truth to that statement.
In science, we very quickly chase after a particular theory as soon as a little bit of evidence is produced that supports it. Gradually, these theories become our basic understanding of a situation, until someone points out the holes in the theory and we have to revise it.
A new theory of Parkinson’s disease has recently been proposed. In today’s post we will review what the theory is suggesting and what evidence there is to support it.
“I still say it’s only a theory”. Source: NewYorker
In the age of ‘alternative facts’, it is always important to remember that we don’t know as much as we think we do. In fact, much of our modern world still relies on a kind of faith rather than actual ‘facts’. For example, we take a particular type of medicine, because it has worked for some people in the past, not because it will definitely make us better.
And the same applies to our understanding of neurodegenerative conditions, like Parkinson’s disease. Based on all the evidence we have collected thus far, we have theories of how Parkinson’s disease may be progressing. But there are always exceptions to the rule, and these force us to refine or reconsider our theories.
Recently a refinement to our theory of Parkinson’s disease has been suggested.
Who has suggested it?
This is Prof Ole Isacson.
He’s a dude.
And this is Dr Simone Engelender.
She’s awesome as well.
She is Associate Professor of Molecular Pharmacology at the Rappaport Family Institute for Research in the Medical Sciences in Haifa, Israel.
Together they have proposed a new theory of Parkinson’s disease that has the research community talking:
Title: The Threshold Theory for Parkinson’s Disease.
Authors: Engelender S, Isacson O.
Journal: Trends Neurosci. 2017 Jan;40(1):4-14.
The new theory proposes that Parkinson’s disease may actually be a ‘systemic condition’ (that is, affecting cells everywhere at the same time), but the clinical features – such as motor issues – only appear as certain thresholds are passed in the affected populations of neurons in the brain.
What does that mean?
Wait a minute. Let’s start at the beginning.
Before discussing what the new theory suggests, shall we first have a look at what the old theories proposed?
Ok, what did the old theory propose?
This is Prof Heiko Braak:
Source – Memim.com
He’s pretty cool too. Nice guy.
Many years ago, Prof Braak – a German neuroanatomist – sat down and examined hundreds of postmortem brains from people with Parkinson’s disease.
He had collected brains from people at different stages of Parkinson’s disease – from just after being diagnosed to having had the condition for decades – and he was looking for any kind of pattern that might explain where and how the disease starts. His research led to what is referred to as the “Braak stages of Parkinson’s disease” – a six step explanation of how the disease spreads up from the brain stem and into the rest of the brain (Click here to read more about this).
The Braak stages of PD. Source: Nature
Braak’s results also led him to propose that Parkinson’s disease may actually begin in the brain stem (which connects the brain to the spinal cord) and the disease slowly works it’s way up into the brain.
That is the ‘ascending’ theory of Parkinson’s disease.
This idea has been further adapted by Braak and others with the discovery of Parkinson’s disease features in the gut (we have discussed this in previous posts – Click here and here to read those posts).
But how does the disease actually spread?
The spread of the condition is believed to be due to the protein alpha synclein being passed between cells in some manner. This idea stemmed from the analysis of the brains of people with Parkinson’s disease who received cell transplantation therapy in the 1980-90’s. After those people passed away (due to natural causes), their brains were analysed and it was discovered that some of the cells in the transplants (1-5%) have Lewy bodies in them (Lewy bodies are one of the hallmarks of Parkinson’s disease, dense circular clusters of proteins including alpha synuclein). This suggests that the disease is passed on to the healthy transplanted cells in some way.
Photos of neurons from the post-mortem brains of people with Parkinson’s that received transplants. White arrows in the images above indicate lewy bodies inside transplanted cells. Source: The Lancet
So the research community has been working with the idea of an ‘ascending’ theory of Parkinson’s disease, and the spreading of the condition via the passing of alpha synuclein from cell to cell. And this theory has been fine,…
Why do I feel like there’s a ‘but’ coming?
Because there is a ‘but’ coming.
And it’s a big BUT.
But as Prof Isacson and Dr Engelender point out there are some holes in this theory.
Some big holes.
For example, in a 2008 study of 71 postmortem brains from people with Parkinson’s disease, 47% of the cases did not fit the predicted ‘Braak theory’ spread of alpha synuclein, and 7% of those cases did not have any cell loss in the dorsal motor nucleus (one of the first sites of damage in the Braak theory – Click here to read more).
Ok, so the theory is not perfect…what are Prof Isacson and Dr Engelender proposing instead?
They suggest that alpha synuclein accumulation starts at about the same time in nerve cells throughout the body, but the different groups of nerve cell differ in how much toxicity they can handle.
Some of these groups of cells can handle a lot (and more than half of the cells need to be lost before clinical features begin to appear), while others have a lower ‘threshold’ (only a few cells need to die before symptoms appear).
Prof Isacson and Dr Engelender argue that the nerve cells around the gut, for example, have a lower reserve (or total number), and, therefore, symptoms related to the gut become more obvious sooner as those cells die off or become less efficient. This lower threshold is in contrast to the more well known cell loss of the dopamine producing neurons in the midbrain, where approximately 50-70 percent of the dopamine neurons disappear before the classical motor features of Parkinson’s start to appear. Their theory suggests that this part of the brain has a larger reserve, and thus higher threshold.
Hence the reason why this is being called the ‘threshold theory’.
Some groups of cells may have a higher threshold in Parkinson’s disease. Source: Cell
Some cells may have a low threshold and only require a few cells to be lost before the clinical features associated with those cells begin to appear. These symptoms would obviously appear earlier than those features associated with a high threshold population of cells, which required substantial loss before symptoms appear.
This idea would explain differing results seen in research findings regarding, for example, vagotomies (the cutting of the vagus nerve to the gut – click here to read more about this). This new theory would suggest that the procedure might not have any impact at all on lowering the risk of Parkinson’s disease.
Both scientists insist that searching for treatments that slow or block the aggregation of alpha synuclein is still necessary.
“Instead of studying how proteins move from one neuron to another and searching for compounds that prevent the ‘spread’ of aggregated alpha-synuclein, we need to study why alpha-synuclein accumulates within neurons and how these neurons die in the disease, and search for compounds that prevent the general neuronal dysfunction,” – Dr Engelender
(Source: Science Daily)
So are there any problems with this new theory?
The new theory is a very interesting idea and deserves consideration. It solves some of the problems with the “ascending theory” discussed further above. But it also faces some of the same problems that the ascending theory has to deal with.
For example, in one large autopsy study which investigated 904 brains, the investigators blindly collected all of the brains that had alpha synuclein present in the groups of neurons that are affected in Parkinson’s disease (eg. the dorsal motor nucleus of vagus, substantia nigra, and/or basal forebrain nuclei.). They found that alpha synuclein was observed in 11.3% (or 106 cases). But when the researchers then looked at the clinical notes associated with those cases, only 32 (30%) had been diagnosed with a neurodegenerative disorder. The rest had demonstrated no clinical features.
Another study found that 8.3% of the aged control brains had alpha synuclein present in them. In addition, the presence of alpha synuclein is not specific to Parkinson’s disease – approximately 50% of people who die with Alzheimer’s disease have been found to have Lewy bodies. These results suggest that alpha synuclein aggregation can be present in both healthy and diseased brains. But if this is so, what role is alpha synuclein playing in Parkinson’s disease?
(You see the sort of problems we are dealing with in research when trying to come up with a theory of how something complicated is actually working?)
What does it all mean?
The central job of a scientist is to test hypotheses.
A hypothesis is a true or false statement (for example, hypothesis: the sun will come up tomorrow – easy to test as the sun either will or won’t come up; the statement is either true or false). In building one hypothesis on top of another hypothesis, we develop theories about how the world around us works.
Sometimes our hypotheses can unwittingly take us in a particular direction, depending on different variables. The danger in this process (one which must be met with discipline and control procedures) is that one can start to look for results that support a hypothesis or theory. It is a very human characteristic to become blind to any evidence to the contrary.
A new theory of Parkinson’s disease has been proposed. It suggests that rather than the condition starting in one location and progressively moving higher into the brain, Parkinson’s disease may actually start everywhere and it is the varying levels of tolerance between different types of cells that determines which cells die first.
It is certainly a new take of the available evidence and the research community is considering it. It will be interesting to see what kind of feedback results from this article, and we will post updates on that feedback as they become available.
The banner for today’s post was sourced from Sott