In American slang, to ‘nix‘ something is to ‘put an end to it’.
Curiously, a protein called NIX may be about to help us put an end to Parkinson’s disease, at least in people with specific genetic mutations.
In today’s post we will look at what NIX is, outline a new discovery about it, and discuss what this new information will mean for people living with Parkinson’s disease.
Sydney harbour. Source: uk.Sydney
Before we start, I would like the reader to appreciate that I am putting trans-Tasman rivalry side here to acknowledge some really interesting research that is being conducted in Australia at the moment.
And this is really interesting.
I have previously spoken a lot about mitochondria and Parkinson’s on this website. For the uninitiated, mitochondria are the power house of each cell. They help to keep the lights on. Without them, the party is over and the cell dies.
Mitochondria and their location in the cell. Source: NCBI
You may remember from high school biology class that mitochondria are tiny bean-shaped objects within the cell. They convert nutrients 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 (some cells have thousands) and highly organised within the cell, being moved around to wherever they are needed.
Like you and I and all other things in life, however, mitochondria have a use-by date.
As mitochondria get old and worn out (or damaged) with time, the cell will recycle them via a process called mitophagy (a blending of the words mitochondria and autophagy – the waste disposal system of each cell).
What does this have to do with Parkinson’s disease?
Well, about 10% of Parkinson’s cases are associated with particular genetic variations that render people vulnerable to developing the condition. Some of these mutations are in sections of DNA (called genes) that provide the instructions for proteins that are involved in the process of mitophagy. Two genes, in particular, are the focus of a lot of Parkinson’s-related research – they are called PARKIN and PINK1.
What do PARKIN and PINK1 do?
This week a group of scientists have published an article which indicates differences between mice and human beings, calling into question the use of these mice in Parkinson’s disease research.
The results could explain way mice do not get Parkinson’s disease, and they may also partly explain why humans do.
In today’s post we will outline the new research, discuss the results, and look at whether Levodopa treatment may (or may not) be a problem.
The humble lab mouse. Source: PBS
Much of our understanding of modern biology is derived from the “lower organisms”.
From yeast to snails (there is a post coming shortly on a snail model of Parkinson’s disease – I kid you not) and from flies to mice, a great deal of what we know about basic biology comes from experimentation on these creatures. So much in fact that many of our current ideas about neurodegenerative diseases result from modelling those conditions in these creatures.
Now say what you like about the ethics and morality of this approach, these organisms have been useful until now. And I say ‘until now’ because an interesting research report was released this week which may call into question much of the knowledge we have from the modelling of Parkinson’s disease is these creatures.
You see, here’s the thing: Flies don’t naturally develop Parkinson’s disease.
Nor do mice. Or snails.
Or yeast for that matter.
So we are forcing a very un-natural state upon the biology of these creatures and then studying the response/effect. Which could be giving us strange results that don’t necessarily apply to human beings. And this may explain our long history of failed clinical trials.
We work with the best tools we have, but it those tools are flawed…
What did the new research report find?
This is the study:
Title: Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson’s disease
Authors: Burbulla LF, Song P, Mazzulli JR, Zampese E, Wong YC, Jeon S, Santos DP, Blanz J, Obermaier CD, Strojny C, Savas JN, Kiskinis E, Zhuang X, Krüger R, Surmeier DJ, Krainc D
Journal: Science, 07 Sept 2017 – Early online publication
The researchers who conducted this study began by growing dopamine neurons – a type of cell badly affected by Parkinson’s disease – from induced pluripotent stem (IPS) cells.
What are induced pluripotent stem cells?
In October 2015, researchers from Georgetown University announced the results of a small clinical trial that got the Parkinson’s community very excited. The study involved a cancer drug called Nilotinib, and the results were rather spectacular.
What happened next, however, was a bizarre sequence of disagreements over exactly what should happen next and who should be taking the drug forward. This caused delays to subsequent clinical trials and confusion for the entire Parkinson’s community who were so keenly awaiting fresh news about the drug.
Earlier this year, Georgetown University announced their own follow up phase II clinical trial and this week a second phase II clinical trial funded by a group led by the Michael J Fox foundation was initiated.
In todays post we will look at what Nilotinib is, how it apparently works for Parkinson’s disease, what is planned with the new trial, and how it differs from the ongoing Georgetown Phase II trial.
The FDA. Source: Vaporb2b
This week the U.S. Food and Drug Administration (FDA) has given approval for a multi-centre, double-blind, randomised, placebo-controlled Phase IIa clinical trial to be conducted, testing the safety and tolerability of Nilotinib (Tasigna) in Parkinson’s disease.
This is exciting and welcomed news.
What is Nilotinib?
Nilotinib (pronounced ‘nil-ot-in-ib’ and also known by its brand name Tasigna) is a small-molecule tyrosine kinase inhibitor, that has been approved for the treatment of imatinib-resistant chronic myelogenous leukemia (CML).
What does any that mean?
Basically, it is the drug that is used to treat a type of blood cancer (leukemia) when the other drugs have failed. It was approved for treating this cancer by the FDA in 2007.
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?
In this post we discuss several recently published research reports suggesting that Parkinson’s disease may be an autoimmune condition. “Autoimmunity” occurs when the defence system of the body starts attacks the body itself.
This new research does not explain what causes of Parkinson’s disease, but it could explain why certain brain cells are being lost in some people with Parkinson’s disease. And such information could point us towards novel therapeutic strategies.
The first issue of Nature. Source: SimpleWikipedia
The journal Nature was first published on 4th November 1869, by Alexander MacMillan. It hoped to “provide cultivated readers with an accessible forum for reading about advances in scientific knowledge.” It has subsequently become one of the most prestigious scientific journals in the world, with an online readership of approximately 3 million unique readers per month (almost as much as we have here at the SoPD).
Each Wednesday afternoon, researchers around the world await the weekly outpouring of new research from Nature. And this week a research report was published in Nature that could be big for the world of Parkinson’s disease. Really big!
On the 21st June, this report was published:
Title: T cells from patients with Parkinson’s disease recognize α-synuclein peptides
Authors: Sulzer D, Alcalay RN, Garretti F, Cote L, Kanter E, Agin-Liebes J, Liong C, McMurtrey C, Hildebrand WH, Mao X, Dawson VL, Dawson TM, Oseroff C, Pham J, Sidney J, Dillon MB, Carpenter C, Weiskopf D, Phillips E, Mallal S, Peters B, Frazier A, Lindestam Arlehamn CS, Sette A
Journal: Nature. 2017 Jun 21. doi: 10.1038/nature22815.
In their study, the investigators collected blood samples from 67 people with Parkinson’s disease and from 36 healthy patients (which were used as control samples). They then exposed the blood samples to fragments of proteins found in brain cells, including fragments of alpha synuclein – this is the protein that is so closely associated with Parkinson’s disease (it makes regular appearances on this blog).
What happened next was rather startling: the blood from the Parkinson’s patients had a strong reaction to two specific fragments of alpha synuclein, while the blood from the control subjects hardly reacted at all to these fragments.
In the image below, you will see the fragments listed along the bottom of the graph (protein fragments are labelled with combinations of alphabetical letters). The grey band on the plot indicates the two fragments that elicited a strong reaction from the blood cells – note the number of black dots (indicating PD samples) within the band, compared to the number of white dots (control samples). The numbers on the left side of the graph indicate the number of reacting cells per 100,000 blood cells.
The investigators concluded from this experiment that these alpha synuclein fragments may be acting as antigenic epitopes, which would drive immune responses in people with Parkinson’s disease and they decided to investigate this further.
A build up of a protein called alpha synuclein inside neurons is one of the characteristic feature of the Parkinsonian brain. This protein is believed to be partly responsible for the loss of dopamine neurons in this condition.
A similar build up of alpha synuclein is also seen in the deadly skin cancer, Melanoma… but those cells don’t die (?!?)… in fact, they just keep on dividing.
Why is there this critical difference?
In today’s post we look at an interesting new study that may have solved this mystery.
A melanoma. Source: Huffington Post
Parkinson’s disease has a very strange relationship with the skin cancer melanoma.
As we have stated in previous posts (Click here, here, here and here to read those posts) people with Parkinson’s disease are 2-8 times more likely to develop melanoma than people without Parkinson’s (And this finding has been replicated a few times: Olsen et al, 2005; Olsen et al, 2006; Driver et al 2007; Gao et al 2009; Lo et al 2010; Bertoni et al 2010;Schwid et al 2010; Ferreira et al, 2010; Inzelberg et al, 2011; Liu et al 2011; Kareus et al 2012; Wirdefeldt et al 2014; Catalá-López et al 2014; Constantinescu et al 2014; Ong et al 2014).
The truly baffling detail in this story, however, is that this relationship is reciprocal – if you have melanoma you are almost 3 times more likely to develop Parkinson’s disease than someone without melanoma (Source: Baade et al 2007; Gao et al 2009).
What is melanoma exactly?
Melanoma is a type of skin cancer.
It develops from the pigment-containing cells known as melanocytes. Melanocytes are melanin-producing cells located in the bottom layer (the stratum basale) of the skin’s outer layer (or epidermis).
The location of melanocytes in the skin. Source: Wikipedia
Melanocytes produce melanin, which is a pigment found in the skin, eyes, and hair. It is also found in the brain in certain types of cells, such as dopamine neurons (where it is referred to as neuromelanin).
Neuromelanin (brown) in dopamine neurons. Source: Schatz
Melanomas are usually caused by DNA damage resulting from exposure to ultraviolet radiation. Ultraviolet radiation from tanning beds increases the risk of melanoma (Source), as does excessive air travel (Source), or simply spending to much time sun bathing.
Approximately 2.2% of men and women will be diagnosed with melanoma at some point during their lives (Source). In women, melanomas most commonly occur on the legs, while in men they are most common on the back. Melanoma makes up 5% of all cancers (Source).
Generally, melanomas is one of the safer cancers, as it can usually be detected early by visual inspection. This cancer is made dangerous, however, by its ability to metastasise (or spread to other organs in the body).
The stages of melanoma. Source: Pathophys
Are there any genetic associations between Parkinson’s disease and melanoma?
When the common genetics mutations that increase the risk of both conditions were previously analysed, it was apparent that none of the known Parkinson’s mutations make someone more susceptible to melanoma, and likewise none of the melanoma-associated genetic mutations make a person vulnerable to Parkinson’s disease (Meng et al 2012;Dong et al 2014; Elincx-Benizri et al 2014).
In fact, researchers have only found very weak genetic connections between two conditions (Click here to read our previous post on this). It’s a real mystery.
Are there any other connections between Parkinson’s disease and melanoma?
Another shared feature of both Parkinson’s disease and melanoma is the build up of a protein called alpha synuclein. Alpha synuclein is believed to be one of the villains in Parkinson’s disease – building up inside a cell, becoming toxic, and eventually killing that cell.
But recently researchers noticed that melanoma also has a build up of alpha synuclein, but those cells don’t die:
Title: Parkinson’s disease-related protein, alpha-synuclein, in malignant melanoma
Authors: Matsuo Y, Kamitani T.
Journal: PLoS One. 2010 May 5;5(5):e10481.
PMID: 20463956 (This article is OPEN ACCESS if you would like to read it)
In this study, researchers from Japan found that alpha synuclein was detected in 86% of the primary and 85% of the metastatic melanoma. Understand that the protein is not detectable in the non-melanoma cancer cells.
So what is it doing in melanoma cells?
Recently, researchers from Germany believe that they have found the answer to this question:
Title: Treatment with diphenyl-pyrazole compound anle138b/c reveals that α-synuclein protects melanoma cells from autophagic cell death
Authors: Turriani E, Lázaro DF, Ryazanov S, Leonov A, Giese A, Schön M, Schön MP, Griesinger C, Outeiro TF, Arndt-Jovin DJ, Becker D
Journal: Proc Natl Acad Sci U S A. 2017 Jun 5. pii: 201700200. doi: 10.1073/pnas.1700200114
In their study, the German researchers looked at levels of alpha synuclein in melanoma cells. They took the melanoma cells that produced the most alpha synuclein and treated those cells with a chemical that inhibits the toxic form of alpha synuclein (which results from the accumulation of the protein).
What they observed next was fascinating: the cell morphology (or physically) changed, leading to massive melanoma cell death. The investigators found that this cell death was caused by instability of mitochondria and a major dysfunction in the autophagy process.
Mitochondria, you may recall, are the power house of each cell. They keep the lights on. Without them, the lights go out and the cell dies.
Mitochondria and their location in the cell. Source: NCBI
Autophagy is the garbage disposal/recycling process within each cell, which is an absolutely essential function. Without autophagy, old proteins and mitochondria will pile up making the cell sick and eventually it dies. Through the process of autophagy, the cell can break down the old protein, clearing the way for fresh new proteins to do their job.
The process of autophagy. Source: Wormbook
Waste material inside a cell is collected in membranes that form sacs (called vesicles). These vesicles then bind to another sac (called a lysosome) which contains enzymes that will breakdown and degrade the waste material. The degraded waste material can then be recycled or disposed of by spitting it out of the cell.
What the German research have found is that the high levels of alpha synuclein keep the mitochondria stable and the autophagy process working at a level that helps to keeps the cancer cell alive.
Next, they replicated this cell culture research in mice with melanoma tumors. When the mice were treated with the chemical that inhibits the toxic form of alpha synuclein, the cancer cancer became malformed and the autophagy process was blocked.
The researchers concluded that “alpha synuclein, which in PD exerts severe toxic functions, promotes and thereby is highly beneficial to the survival of melanoma in its advanced stages”.
So what does all of this mean for Parkinson’s disease?
Well, this is where the story gets really interesting.
You may be pleased to know that the chemical (called Anle138b) which was used to inhibit the toxic form of alpha synuclein in the melanoma cells, also works in models of Parkinson’s disease:
Title: Anle138b: a novel oligomer modulator for disease-modifying therapy of neurodegenerative diseases such as prion and Parkinson’s disease.
Authors: Wagner J, Ryazanov S, Leonov A, Levin J, Shi S, Schmidt F, Prix C, Pan-Montojo F, Bertsch U, Mitteregger-Kretzschmar G, Geissen M, Eiden M, Leidel F, Hirschberger T, Deeg AA, Krauth JJ, Zinth W, Tavan P, Pilger J, Zweckstetter M, Frank T, Bähr M, Weishaupt JH, Uhr M, Urlaub H, Teichmann U, Samwer M, Bötzel K, Groschup M, Kretzschmar H, Griesinger C, Giese A.
Journal: Acta Neuropathol. 2013 Jun;125(6):795-813
PMID: 23604588 (This article is OPEN ACCESS if you would like to read it)
In this first study the researchers discovered Anle138b by conducted a large screening study to identify for molecules that could inhibit the toxic form of alpha synuclein.
They next tested Anle138b in both cell culture and rodent models of Parkinson’s disease and found it to be neuroprotective and very good at inhibiting the toxic form of alpha synuclein. And the treatment looks to be very effective. In the image below you can see dark staining of toxic alpha synuclein in the left panel from the brain of an untreated mouse, but very little staining in the right panel from an Anle138b treated mouse.
Toxic form of alpha synuclein (dark staining). Source: Max-Planck
Importantly, Anle138b does not interfere with normal behaviour of alpha synuclein in the mice (such as production of the protein, correct functioning, and eventual degradation/disposal of the protein), but it does act as an inhibitor of alpha synuclein clustering or aggregation (the toxic form of the protein). In addition, the investigators found no toxic effects of Anle138b in any of their experiments even after long-term high-dose treatment (more than one year).
And in a follow up study, the drug was effective even if it was given after the disease model had started:
Title: The oligomer modulator anle138b inhibits disease progression in a Parkinson mouse model even with treatment started after disease onset
Authors: Levin J, Schmidt F, Boehm C, Prix C, Bötzel K, Ryazanov S, Leonov A, Griesinger C, Giese A.
Journal: Acta Neuropathol. 2014 May;127(5):779-80.
PMID: 24615514 (This article is OPEN ACCESS if you would like to read it)
During the first study, the researchers had started Anle138b treatment in the mouse model of Parkinson’s disease at a very young age. In this study, however, the investigators began treatment only as the symptoms were starting to show, and Anle138b was found to significantly improve the overall survival of the mice.
One particularly interesting aspect of Anle138b function in the brain is that it does not appear to change the level of the autophagy suggesting that the biological effects of treatment with Anle138b is cell-type–specific (Click here to read more about this). In cancer cells, it is having a different effect to that in brain cells. These differences in effect may also relate to disease conditions though, as Anle138b was not neuroprotective in a mouse model of Multiple System Atrophy (MSA; Click here to read more about this).
Is Anle138b being tested in the clinic?
Ludwig-Maximilians-Universität München and the Max Planck Institute for Biophysical Chemistry (Göttingen) have spun off a company called MODAG GmbH that is looking to advance Anle138b to the clinic (Click here for the press release). The Michael J Fox Foundation are helping to fund more preclinical development of this treatment (Click here to read more about this).
We will be watching their progress with interest.
What does it all mean?
Summing up: There are many mysteries surrounding Parkinson’s disease, but some researchers from Germany may have just solved one of them and at the same time developed a potentially useful new treatment.
They have discovered that the Parkinson’s associated protein, alpha synuclein, which is produced in large amounts in the skin cancer melanoma, is actually playing an important role in keeping those cancer cells alive. By finding a molecule that can block the build up of alpha synuclein, they have not only found a treatment for melanoma, but also potentially one for Parkinson’s disease.
And given that both diseases are closely associated, this could be seen as a great step forward. Two birds with one stone as the saying goes.
The banner for today’s post was sourced from Wikipedia
When people in England think of the city of Sheffield, quite often images of a great industrial past will come to mind.
They usually don’t think of the flies, fish and (yes) a Tigar (no, not a typo!) that are influencing Parkinson’s disease research in the city.
In today’s post we will look at how the re-invention of a city could have a major impact on Parkinson’s disease.
The industrial heritage of Sheffield. Source: SIMT
It is no under statement to say that the history of Sheffield – a city in South Yorkshire, England – is forged in steel.
In his 1724 book, “A tour thro’ the whole island of Great Britain“, the author Daniel Defoe wrote of Sheffield:
“Here they make all sorts of cutlery-ware, but especially that of edged-tools, knives, razors, axes, &. and nails; and here the only mill of the sort, which was in use in England for some time was set up, for turning their grindstones, though now ’tis grown more common”
Sheffield has a long history of metal work, thanks largely to its geology: The city is surrounded by fast-flowing rivers and hills containing many of the essential raw materials such as coal and iron ore.
And given this fortunate circumstance and an industrious culture, the city of Sheffield particularly prospered during the industrial revolution of the mid-late 1800s (as is evident from the population growth during that period).
The population of Sheffield over time. Source: Wikipedia
But traditional manufacturing in Sheffield (along with many other areas in the UK) declined during the 20th century and the city has been forced to re-invent itself in the early 21st century. And this time, rather than taking advantage of their physical assets, the city is focusing on its mental resources.
Great. Interesting stuff. Really. But what does this have to do with flies, fish and Parkinson’s disease???
Indeed. Let’s get down to business.
The Sheffield Institute for Translational Neuroscience (SITraN) was officially opened in 2010 by Her Majesty The Queen. It is the first European Institute purpose-built and dedicated to basic and clinical research into Motor Neuron Disease as well as related neurodegenerative disorders such as Parkinson’s and Alzheimer’s disease.
Since its opening, the institute has published some pretty impressive research, particularly in the field of Parkinson’s disease.
And here is where we get to the flies:
Pink flies. Source: Wallpapersinhq
We have previously discussed “Pink” flies and their critical role in Parkinson’s research (Click here to read that post).
Today we are going to talk about Lrrk2 flies.
What is Lrrk2?
This is Sergey Brin.
He’s a dude.
One of the founders of the search engine company “Google”. Having changed the world, he is now turning his attention to other projects.
One of those other projects is close to our hearts: Parkinson’s disease.
In 1996, Sergey’s mother started experiencing numbness in her hands. Initially it was believed to be RSI (Repetitive strain injury). But then her left leg started to drag. In 1999, following a series of tests, Sergey’s mother was diagnosed with Parkinson’s disease. It was not the first time the family had been affected by the condition: Sergey’s late aunt had also had Parkinson’s disease.
Both Sergey and his mother have had their DNA scanned for mutations that increase the risk of Parkinson’s disease. And they discovered that they were both carrying a mutation on the 12th chromosome, in a gene called PARK8 – one of the Parkinson’s disease associated genes. Autosomal dominant mutations (meaning if you have just one copy of the mutated gene) in the PARK8 gene dramatically increase one’s risk of developing Parkinson’s disease.
PARK8 provides the instructions for making an enzyme called Leucine-rich repeat kinase 2 (or Lrrk2).
The structure of Lrrk2. Source: Wikipedia
Also known as ‘Dardarin‘ (from the Basque word “dardara” which means trembling), Lrrk2 has many functions within a cell – from helping to move things around inside the cell to helping to keep the power on (involved with mitochondrial function).
Now, not everyone with this particular mutation will go on to develop Parkinson’s disease, and Sergey has decided that his chances are 50:50. But he does not appear to be taking any chances though. Being one of the founders of a large company like Google, has left Sergey with considerable resources at his disposal. And he has chosen to focus some of those resources on Lrrk2 research (call it an insurance policy). He has done this via considerable donations to groups like the Michael J Fox foundation.
Actor Michael J Fox was diagnosed at age 30. Source: MJFox foundation
So just as Pink flies derive their name from mutations in the Parkinson’s associated Pink1 gene, Lrrk2 flies have mutations in the Lrrk2 gene.
So what have the researchers at Sheffield done with the Lrrk2 flies?
In 2013, the Sheffield researchers published an interesting research report:
Title: Ursocholanic acid rescues mitochondrial function in common forms of familial Parkinson’s disease
Authors: Mortiboys H, Aasly J, Bandmann O.
Journal: Brain. 2013 Oct;136(Pt 10):3038-50.
In this study, the investigators took 2000 drugs (including 1040 licensed drugs and 580 naturally occurring compounds) and conducted a massive screen to identify drugs that could rescue mitochondrial dysfunction in PARK2 (Pink1) mutant cells.
Mitochondria are the power house of each cell. They keep the lights on. Without them, the lights go out and the cell dies.
Mitochondria and their location in the cell. Source: NCBI
In certain genetic forms of Parkinson’s disease (such as those associated with mutations in the PARK2 gene), the mitochondria in cells becomes dysfunctional and may not be disposed of properly (Click here to read our previous post related to this).
In their huge screen of 2000 drugs, the researchers in Sheffield identified 15 drugs that could rescue the mitochondria dysfunction in the PARK2 skins cells. Of those 15 compounds, two were chosen for further functional studies. They were:
- Ursocholanic acid
- Dehydro(11,12)ursolic acid lactone
Neither ursocholanic acid nor dehydro(11,12)ursolic acid lactone are FDA-licensed drugs. We have little if any information regarding their use in humans. Given this situation, the researchers turned their attention to the chemically related bile acid ‘ursodeoxycholic acid’, which has been in clinical use for more than 30 years.
What is Ursodeoxycholic Acid?
Ursodeoxycholic Acid (or UDCA) is a drug that is used to to improve bile flow and reduce gallstone formation. In the USA it is also known as ‘ursodiol’.
Ursodiol. Source: Wikimedia
Bile is a fluid that is made and released by your liver, and it stored in the gallbladder. Its function is to help us with digestion. UDCA occurs naturally in bile – it is basically a bile acid and can therefore be useful in dissolving gallstones. UDCA has been licensed for the treatment of patients since 1980. UDCA also reduces cholesterol absorption.
So what did the Sheffield researchers find with UDCA?
The researchers tested UDCA on mitochondrial function in PARK2 skin cells, and they found that the drug rescued the cells. They then tested UDCA on skin cells from people with Parkinson’s disease who had mutations in the PARK8 (Lrrk2) gene (G2019S).
The researchers had previously found impaired mitochondrial function and morphology in skin cells taken from people with PARK8 associated Parkinson’s disease (Click here to read more about this), and other groups had reported similar findings (Click here for more on this).
And when they treated the Lrrk2 cells with UDCA, guess what happened?
UDCA was able to rescue the mitochondrial effect in those cells as well!
Obviously these results excited the Sheffield scientists and they set up a collaboration with researchers at York University and from Norway, to look at the potential of UDCA in rescuing the fate of Lrrk2 flies. The results of that study were published two years ago:
Title: UDCA exerts beneficial effect on mitochondrial dysfunction in Lrrk2 (G2019S) carriers and in vivo.
Authors: Mortiboys H, Furmston R, Bronstad G, Aasly J, Elliott C, Bandmann O.
Journal: Neurology. 2015 Sep 8;85(10):846-52.
PMID: 26253449 (This article is OPEN ACCESS if you would like to read it).
The researchers tested UDCA on flies (or drosophila) with specific Lrrk2 mutations (G2019S) display a progressive loss of photoreceptor cell function in their eyes. The mitochondria in the photoreceptor are swollen and disorganised. When the investigators treated the flies with UDCA, they found approximately 70% rescue of the photoreceptor cells function.
The researchers in Sheffield concluded that UDCA has a marked rescue effect on cells from a Parkinson’s disease-associated gene mutation model, and they proposed that “mitochondrial rescue agents may be a promising novel strategy for disease-modifying therapy in Lrrk2-related PD, either given alone or in combination with Lrrk2 kinase inhibitors” (for more information about the Lrrk2 inhibitors they refer, click here).
And the good news regarding this line of research: other research groups have also observed similar beneficial effects with UDCA in models of Parkinson’s disease:
Title: Ursodeoxycholic acid suppresses mitochondria-dependent programmed cell death induced by sodium nitroprusside in SH-SY5Y cells.
Authors: Chun HS, Low WC.
Journal: Toxicology. 2012 Feb 26;292(2-3):105-12.
This research group also demonstrated that UDCA could reduce cell death in a cellular model of Parkinson’s disease.
And this study was followed by another one from a different research group, which involved testing UDCA in animals:
Title: Ursodeoxycholic Acid Ameliorates Apoptotic Cascade in the Rotenone Model of Parkinson’s Disease: Modulation of Mitochondrial Perturbations.
Authors: Abdelkader NF, Safar MM, Salem HA.
Title: Mol Neurobiol. 2016 Mar;53(2):810-7.
These researchers found UDCA rescued a rodent model of Parkinson’s disease (involving the neurotoxin rotenone). UDCA not only improved mitochondrial performance in the rats, but also demonstrated anti-inflammatory and anti-cell death properties.
Given all this research, the Sheffield researchers are now keen to test UDCA in clinical trials for Parkinson’s disease.
Has anyone tested UDCA in the clinic for Parkinson’s disease?
Not that we are aware of, but two groups are interested in attempting it.
Firstly, the University of Minnesota – Clinical and Translational Science Institute has registered a trial (Click here to read more about this). This trial will not, however, be testing efficacy of the drug on Parkinson’s symptoms. It will focus on measuring UDCA levels in individuals after four weeks of repeated high doses of oral UDCA (50mg/kg/day), and determining the bioenergetic profile and ATPase activity in those participants. Basically, they want to see if UDCA is safe and active in people with Parkinson’s disease.
EDITOR’S NOTE HERE: Before we move on, the team at the SoPD would like to say that while UDCA is a clinically available drug, it is still experimental for Parkinson’s disease. There is no indication yet that it has beneficial effects in people with Parkinson’s disease. In addition, UDCA is also is known to have side effects, which include flu symptoms, nausea, diarrhea, and back pain. And individuals have been known to have allergic reactions to UDCA treatment (Click here and here for more on the side effects of UDCA). Thus we must impress caution on anyone planning to experiment with this drug. Before attempting any kind of change in a current treatment regime, PLEASE discuss your plans with a medically qualified physician who is familiar with your case history.
Ok, so that was the flies research, what about the fish? And the… uh, tigar?
Yes. The fish are called Zebrafish (or Danio rerio).
They are a tropical freshwater fish that is widely used in biological research.
Biology researchers love these little guys because their genome has been fully sequenced and they has well characterised and testable behaviours. In addition, their development is very rapid (3 months), and its embryos are large and transparent.
And the researchers at Sheffield are using these fish to study Parkinson’s disease.
How did they do that?
Title: TigarB causes mitochondrial dysfunction and neuronal loss in Pink1 deficiency
Authors: Flinn LJ, Keatinge M, Bretaud S, Mortiboys H, Matsui H, De Felice E, Woodroof HI, Brown L, McTighe A, Soellner R, Allen CE, Heath PR, Milo M, Muqit MM, Reichert AS, Köster RW, Ingham PW, Bandmann O.
Journal: Ann Neurol. 2013 Dec;74(6):837-47.
PMID: 24027110 (This article is OPEN ACCESS if you would like to read it)
Firstly, the group at Sheffield generated zebrafish that had a mutation in the Parkinson’s associated gene ‘PARK6’. This gene provides the plans for the production of a protein called Pink1 (we have previously discussed Pink1 – click here to read more on this).
In normal healthy cells, the Pink1 protein is absorbed by mitochondria and eventually degraded as it is not used. In unhealthy cells, however, this process becomes inhibited and Pink1 starts to accumulate on the outer surface of the mitochondria. Sitting on the surface, it starts grabbing another Parkinson’s associated protein called Parkin. This pairing is a signal to the cell that this particular mitochondria is not healthy and needs to be removed.
Pink1 and Parkin in normal (right) and unhealthy (left) situations. Source: Hindawi
The process by which mitochondria are removed is called mitophagy. Mitophagy is part of the autophagy process, which is an absolutely essential function in a cell. Without autophagy, old proteins and mitochondria will pile up making the cell sick and eventually it dies. Through the process of autophagy, the cell can break down the old protein, clearing the way for fresh new proteins to do their job.
Think of autophagy as the waste disposal/recycling process of the cell.
The process of autophagy. Source: Wormbook
Waste material inside a cell is collected in membranes that form sacs (called vesicles). These vesicles then bind to another sac (called a lysosome) which contains enzymes that will breakdown and degrade the waste material. The degraded waste material can then be recycled or disposed of by spitting it out of the cell.
In the case of a PARK6 mutations, Pink1 protein can not function properly with Parkin and the autophagy process breaks down. As a result, the old or unhealthy mitochondria start to pile up in the cell, resulting in the cell getting sick and dying.
Now back to the Zebrafish.
When the Sheffield researchers mutated PARK6 in the zebrafish, they noticed that the fish had a very early and persistent loss of dopamine neurons in their brains. These fish also had enlarged, unhealthy mitochondria and reduced mitochondrial activity.
Given this result, the investigators next wanted to identify which genes have increased or decreased levels of activity as a result of this genetic manipulation. They identified 108 genes that were higher in the PARK6 mutant, and 146 genes had lower activity.
One gene in particular had activity levels 12 times higher in the PARK6 mutant fish than the normal zebrafish.
The name of that gene? TP53-Induced Glycolysis And Apoptosis Regulator (or Tigar).
What is Tigar?
Tigar is a gene that provides the instructions for making a protein that is activated by p53 (also known as TP53).
What does that mean?
p53 is a protein that has three major functions: controlling cell division, DNA repair, and apoptosis (or cell death). p53 performs these functions as a transcriptional activator (that is a protein that binds to DNA and helps produce RNA (the process of transcription) – see our previous post explaining this).
p53 protein structure, bound to DNA (in gold). Source: Wikipedia
In regulating the cell division, p53 prevents cells from dividing too much and in this role it is known as a tumour suppression – it suppresses the emergence of cancerous tumours. Genetic mutations in the p53 gene result in run away cell division, and (surprise!) as many as 50% of all human tumours contain mutations in the p53 gene.
Cancer vs no cancer. Source: Khan Academy
In DNA repair, p53 is sometimes called “the guardian of the genome” as it prevents mutations and helps to conserve stability in the genome. This function also serves to prevent the development of cancer, by helping to repair potentially cancer causing mutations….and in this role it is known as a tumour suppression. Obviously, if there is a mutation in the p53 gene, less DNA repair will occur – increasing the risk of cancer occurring.
And finally, in cell death, p53 plays a critical role in telling a cell when to die. And (continuing with the cancer theme), if there is a mutation in the p53 gene, fewer cells will be told to die – increasing the risk of cancer occurring. And in this role p53 is known as a tumour suppression.
In normal cells, the levels of p53 protein are usually low. When a cell suffers DNA damage and stress, there is often an increase in the amount of p53 protein. If this increases past a particular threshold, then the cell will be instructed to die.
If you haven’t guessed yet, p53 is a major player inside most cell, and it controls the activity of a lot of genes.
And one of those genes is Tigar.
But what does Tigar actually do?
So we have explained the “TP53-Induced” part of the “TP53-Induced Glycolysis And Apoptosis Regulator” name, let’s now focus on the “Glycolysis And Apoptosis Regulator”
Tigar is an interesting protein because it is an enzyme that primarily functions as a regulator of the breaking down of glucose (“Glycolysis” involves the conversion of glucose into a chemical called pyruvate). In addition to this role, however, Tigar acts in preventing cell death (or apoptosis).
Increased levels of Tigar protects cells from oxidative-stress induced apoptosis, by decreasing the levels of free radicals. In this way, it promotes anti-oxidant activities.
But hang on a second, anti-oxidant activity should be good for the cell right? Why are the dopamine cells are dying if Tigar levels are increasing in the PARK6 mutants?
The answer: TIGAR is also a negative regulator of a process called mitophagy. As we discussed above, mitophagy is the process of removing mitochondria by autophagy. Increases in the levels of TIGAR blocks mitophagy in a cell, and results in an increased number of swollen and unhealthy mitochondria in those cells (Click here to read more about this). These swollen mitochondria are comparable to the enlarged mitochondria identified the PARK6 zebrafish by the Sheffield researchers.
And the researchers believe that this may be the cause of the cell death in the PARK6 zebrafish – the double impact of PARK6 and Tigar induced problems with mitophagy.
NOTE: Problems with mitophagy is believed to be an important mechanism in the development of early-onset Parkinson’s disease (Click here for a recent review on this)
Ok, and what did the Sheffield researchers do next?
Given that there was such a huge increase in Tigar levels in the PARK6 zebrafish, the investigators decided to reduce Tigar levels in the PARK6 zebrafish to see what impact this would have on the fish (and their mitochondria).
Remarkably, reductions of Tigar levels resulted in complete rescue of the dopamine neurons in the PARK6 fish. It also increased mitochondrial activity in those cells, and reduced the activation of the microglia cells, which can also play a role in the removal of sick cells in the brain.
The researchers concluded that the results demonstrate that TIGAR is “a promising novel target for disease‐modifying therapy in Pink1‐related Parkinson’s disease”.
And what are the researchers planning to do next with Tigar?
Prof Oliver Bandmann, the senior scientist who ran the study, has said that they “need to finish studying TIGAR levels in the brains of people with Parkinson’s and want to better understand how this protein is involved in maintaining the cell batteries – called ‘mitochondria'” (Source).
Our guess is that the group will also be conducting studies looking at Tigar reduction in rodent models of Parkinson’s disease to determine if this is a viable target in mammals. If Tigar reduction in rodents is found to be effective, the researchers will probably turn their attention to drug screening studies to identify currently available drugs that can reduce the activity of Tigar. Such a drug would provide us with yet another potential treatment for Parkinson’s disease.
We’ll be keeping an eye out for these pieces of research.
This is all very interesting. What does the future hold for Parkinson’s research in Sheffield?
Well, in a word: Keapstone.
Source: Parkinson’s UK
The goal of the company – the first of its kind – is to combine world-leading research from the University with funding and expertise from the charity to help develop revolutionary drugs for Parkinson’s disease.
What is virtual about it? The biotech won’t be building its own labs, employing a team of specialist laboratory scientists, or buying any high-tech equipment (which would all be incredibly expensive). Rather they will form partnerships with groups that do specific tasks the best.
Here is a video of Dr Author Roach (director of Research at Parkinson’s UK) explaining the idea behind this endeavour:
By seeking a collaboration with Sheffield in the creation of a spin-out biotech company, Parkinson’s UK is not only acknowledging Sheffield’s track record, but also making an investment in their future research. While we cannot be entirely sure of what the long-term future holds for Parkinson’s research in Sheffield, we do know that Keapstone will be an important aspect of it in the immediate future.
Could this be a model for the future of Parkinson’s disease research? Only time will tell. We will have a closer look at Keapstone Therapeutics in an upcoming post.
Click here to learn more about the virtual biotech project.
So what does it all mean?
In 2017, we here at the SoPD have decided to begin highlighting some of the Parkinson’s disease research centres as an addition feature on the blog. We have not been approached by the research group in Sheffield or the University itself, and our selection of this city as our first case study was based purely on the fact that we really like what is happening there with regards to Parkinson’s research!
The research group in Sheffield has undertaken multiple lines of research which could potentially providing us with several novel treatment options for Parkinson’s disease. These lines of research have focused not only on clinically available drugs, but also identifying novel targets. We like what they are doing and will keep a close eye on progress there.
And over the next year we will select additional centres of Parkinson’s research based on the same criteria (us liking what they are doing). Our next case study will be the Van Andel Research Institute in Grand Rapids, Michigan (we would hate to be accused of having a UK bias).
EDITORIAL NOTE: Under absolutely no circumstances should anyone reading the material on this website consider it medical advice. The information provided here is for educational purposes only. Before considering or attempting any change in your treatment regime, PLEASE consult with your doctor or neurologist. While some of the drugs discussed on this website are clinically available, they may have serious side effects. We urge caution and professional consultation before altering any treatment regime. SoPD can not be held responsible for any actions taken based on the information provided here.
The banner for today’s post was sourced from TotalProduceLocal
Recently it has been announced that the Parkinson’s disease-associated gene PARK2 was found to be mutated in 1/3 of all types of tumours analysed in a particular study.
For people with PARK2 associated Parkinson’s disease this news has come as a disturbing shock and we have been contacted by several frightened readers asking for clarification.
In today’s post, we put the new research finding into context and discuss what it means for the people with PARK2-associated Parkinson’s disease.
The As, the Gs, the Ts, and the Cs. Source: Cavitt
The DNA in almost every cell of your body provides the template for making a human being.
All the necessary information is encoded in that amazing molecule. The basic foundations of that blueprint are the ‘nucleotides’ – which include the familiar A, C, T & Gs – that form pairs (called ‘base pairs’) and which then join together in long strings of DNA that we call ‘chromosomes’.
The basics of genetics. Source: CompoundChem
If DNA provides the template for making a human being, however, it is the small variations (or ‘mutations’) in our individual DNA that ultimately makes each of us unique. And these variations come in different flavours: some can simply be a single mismatched base pair (also called a point-mutation or single nucleotide variant), while others are more complicated such as repeating copies of multiple base pairs.
Lots of different types of genetic variations. Source: Nature
Most of the genetic variants that define who we are, we have had since conception, passed down to us from our parents. These are called ‘germ line’ mutations. Other mutations, which we pick up during life and are usually specific to a particular tissue or organ in the body (such as the liver or blood), are called ‘somatic’ mutations.
Somatic vs germ line mutations. Source: AutismScienceFoundation
In the case of germ line mutations, there are several sorts. A variant that has to be provided by both the parents for a condition to develop, is called an ‘autosomal recessive‘ variant; while in other cases only one copy of the variant – provided by just one of the parents – is needed for a condition to appear. This is called an ‘autosomal dominant’ condition.
Autosomal dominant vs recessive. Source: Wikipedia
Many of these tiny genetic changes infer benefits, while other variants can result in changes that are of a more serious nature.
What does genetics have to do with Parkinson’s disease?
Approximately 15% of people with Parkinson disease have a family history of the condition – a grandfather, an aunt or cousin. For a long time researchers have noted this familial trend and suspected that genetics may play a role in the condition.
About 10-20% of Parkinson’s disease cases can be accounted for by genetic variations that infer a higher risk of developing the condition. In people with ‘juvenile-onset’ (diagnosed under the age 20) or ‘early-onset’ Parkinson’s disease (diagnosed under the age 40), genetic variations can account for the majority of cases, while in later onset cases (>40 years of age) the frequency of genetic variations is more variable.
For a very good review of the genetics of Parkinson’s disease – click here.
There are definitely regions of DNA in which genetic variations can increase one’s risk of developing Parkinson’s disease. These regions are referred to as ‘PARK genes’.
What are PARK genes?
We currently know of 23 regions of DNA that contain mutations associated with increased risk of developing Parkinson’s disease. As a result, these areas of the DNA have been given the name of ‘PARK genes’.
The region does not always refer to a particular gene, for example in the case of our old friend alpha synuclein, there are two PARK gene regions within the stretch of DNA that encodes alpha synuclein – that is to say, two PARK genes within the alpha synuclein gene. So please don’t think of each PARK genes as one particular gene.
There can also be multiple genetic variations within a PARK gene that can increase the risk of developing Parkinson’s disease. The increased risk is not always the result of one particular mutation within a PARK gene region (Note: this is important to remember when considering the research report we will review below).
In addition, some of the mutations within a PARK gene can be associated with increased risk of other conditions in addition to Parkinson’s disease.
And this brings us to the research report that today’s post is focused on.
One of the PARK genes (PARK2) has recently been in the news because it was reported that mutations within PARK2 were found in 2/3 of the cancer tumours analysed in the study.
Here is the research report:
Title: PARK2 Depletion Connects Energy and Oxidative Stress to PI3K/Akt Activation via PTEN S-Nitrosylation
Authors: Gupta A, Anjomani-Virmouni S, Koundouros N, Dimitriadi M, Choo-Wing R, Valle A, Zheng Y, Chiu YH, Agnihotri S, Zadeh G, Asara JM, Anastasiou D, Arends MJ, Cantley LC, Poulogiannis G
Journal: Molecular Cell, (2017) 65, 6, 999–1013
PMID: 28306514 (This article is OPEN ACCESS if you would like to read it)
The investigators who conducted this study had previously found that mutations in the PARK2 gene could cause cancer in mice (Click here to read that report). To follow up this research, they decided to screen the DNA from a large number of tumours (more than 20,000 individual samples from at least 28 different types of tumours) for mutations within the PARK2 region.
Remarkably, they found that approximately 30% of the samples had PARK2 mutations!
In the case of lung adenocarcinomas, melanomas, bladder, ovarian, and pancreatic, more than 40% of the samples exhibited genetic variations related to PARK2. And other tumour samples had significantly reduced levels of PARK2 RNA. For example, two-thirds of glioma tumours had significantly reduced levels of PARK2 RNA.
Hang on a second, what is PARK2?
PARK2 is a region of DNA that has been associated with Parkinson’s disease. It lies on chromosome 6. You may recall from high school science class that a chromosomes is a section of our DNA, tightly wound up to make storage in cells a lot easier. Humans have 23 pairs of chromosomes.
Several genes fall within the PARK2 region, but most of them are none-protein-coding genes (meaning that they do not give rise to proteins). The PARK2 region does produce a protein, which is called Parkin.
The location of PARK2. Source: Atlasgeneticsoncology
Particular genetic variants within the PARK2 regions result in an autosomal recessive early-onset form of Parkinson disease (diagnosed before 40 years of age). One recent study suggested that as many as half of the people with early-onset Parkinson’s disease have a PARK2 variation.
Click here for a good review of PARK2-related Parkinson’s disease.
Ok, so if PARK2 was about Parkinson’s disease, what is it doing in cancer?
In Parkinson’s disease, Parkin – the protein of PARK2 – is involved with the removal/recycling of rubbish from the cell. But Parkin has also been found to have other functions. Of particular interest is the ability of Parkin to encourage dividing cells to…well, stop dividing. We do not see this function in neurons, because neurons do not divide. In rapidly dividing cells, however, Parkin can apparently stop the cells from dividing:
Title: Parkin induces G2/M cell cycle arrest in TNF-α-treated HeLa cells
Authors: Lee MH, Cho Y, Jung BC, Kim SH, Kang YW, Pan CH, Rhee KJ, Kim YS.
Journal: Biochem Biophys Res Commun. 2015 Aug 14;464(1):63-9.
This discovery made researchers re-designate PARK2 as a ‘tumour suppressor‘ – a gene that encodes a protein which can block the development of tumours. Now, if there is a genetic variant within a tumour suppressor – such as PARK2 – that blocks it from stopping dividing cells, there is the possibility of the cells continuing to divide and developing into a tumour.
Without a properly functioning Parkin protein, rapidly dividing cells may just keep on dividing, encouraging the growth of a tumour.
Interestingly, the reintroduction of Parkin into cancer cells results in the death of those cells – click here to read more on this.
Oh no, I have a PARK2 mutation! Does this mean I am going to get cancer?
Let us be very clear: It does not mean you are ‘going to get cancer’.
And there are two good reasons why not:
Firstly, location, location, location – everything depends on where in the Parkin gene a mutation actually lies. There are 10 common mutations in the Parkin gene that can give rise to early-onset Parkinson’s disease, but only two of these are associated with an increased risk of cancer (they are R24P and R275W – red+black arrow heads in the image below – click here to read more about this).
Comparing PARK2 Cancer and PD associated mutations. Source: Nature
Parkin (PARK2) is one of the largest genes in humans (of the 24,000 protein encoding genes we have, only 18 are larger than Parkin). And while size does not really matter with regards to genetic mutations and cancer (the actual associated functions of a gene are more critical), given the size of Parkin it isn’t really surprising that it has a high number of trouble making mutations. But only two of the 13 cancer causing mutations are related to Parkinson’s.
Thus it is important to beware of exactly where your mutation is on the gene.
Second, in general, people with Parkinson’s disease actually have a 20-30% decreased risk of cancer (after you exclude melanoma, for which there is an significant increased risk and everyone in the community should be on the lookout for). There are approximately 140 genes that can promote or ‘drive’ tumour formation. But a typical tumour requires mutations in two to more of these “driver gene” for a tumour to actually develop. Thus a Parkin cancer-related mutation alone is very unlikely to cause cancer by itself.
So please relax.
The new research published this week is interesting, but it does not automatically mean people with a PARK2 mutation will get cancer.
What does it all mean?
So, summing up: Small variations in our DNA can play an important role in our risk of developing Parkinson’s disease. Some of those Parkinson’s associated variations can also infer risk of developing other diseases, such as cancer.
Recently new research suggested that genetic variations in a Parkinson’s associated genetic region called PARK2 (or Parkin) are found in many forms of cancer. While the results of this research are very interesting, in isolation this information is not useful except in frightening people with PARK2 associated Parkinson’s disease. Cancers are very complex. The location of a mutation within a gene is important and generally more than cancer-related gene needs to be mutated before a tumour will develop.
The media needs to be more careful with how they disseminate this information from new research reports. People who are aware that they have a particular genetic variation will be sensitive to any new information related to that genetic region. They will only naturally take the news badly if it is not put into proper context.
So to the frightened PARK2 readers who contacted us requesting clarification, firstly: keep calm and carry on. Second, ask your physician about where exactly your PARK2 variation is exactly within the gene. If you require more information from that point on, we’ll be happy to help.
The banner for today’s post was sourced from Ilovegrowingmarijuana
We all suffer it. Whether it is work related, relationship related, or simply self-induced, we humans foolishly put a great deal of pressure on our bodies.
Many pieces of research suggest that this pressure takes a toll on our health, which could lead to long-term conditions like Parkinson’s disease.
Recently some Korean researchers have identified a stress-related hormone that could have beneficial effects for Parkinson’s disease.
In today’s post, we will review their recently published research and look at what it means for people with Parkinson’s disease.
Shortly before leaving the role of President of the United States of America, ex-President Barrack Obama was asked about the stress that comes with the job, and his answer was interesting. He suggested that it is important to take a ‘long view’ of events and not to get bogged down by the weight of everything going on around you:
Despite these sage words, it is difficult not to notice the impact that his previous job has had on the man:
What a stress can do to a person. Source: Reddit
Stress seems to be a major part of modern life for many people – some people even indicate that they need it and that they thrive on it. But this pressure that we put on our bodies tends to have a damaging effect on our general health. And there is evidence that that stress may even lead to long term consequences such as cancer and neurodegenerative conditions such as Parkinson’s disease.
Causality, however, is very difficult to determine in science.
The best we can do is suggest that a particular variable (such as stress) may increase one’s risk of developing a particular condition (such as Parkinson’s disease).
So what do we know about stress and Parkinson’s disease?
This is Professor Bas Bloem.
Prof Bloem – no stress here. Source: NRC
Professor Bloem is a consultant neurologist at the Department of Neurology, Radboud University Nijmegen Medical Centre (the Netherlands). He is also one of the researchers behind ParkinsonNet – an innovative healthcare concept that now consists of 64 professional networks for people with Parkinson’s disease covering all of the Netherlands.
In 2010, his research group noticed something interesting:
Title: Artistic occupations are associated with a reduced risk of Parkinson’s disease.
Authors: Haaxma CA, Borm GF, van der Linden D, Kappelle AC, Bloem BR.
Journal: J Neurol. 2015 Sep;262(9):2171-6.
PMID: 26138540 (This article is OPEN ACCESS if you would like to read it)
In their study, Prof Bloem and his colleagues conducted a case–controlled analysis of 750 men with Parkinson’s disease (onset ≥40 years) and 1300 healthy men, which involved the participants completing a questionnaire about their occupational history. As expected (based on previous reports), they found that farming was associated with an increased risk of developing Parkinson’s disease (click here for more on this).
Interestingly, artistic occupations late in life were associated with a reduced risk of subsequent Parkinson’s disease. Another interesting observation from the study was that no initial occupation (early in life) predicted Parkinson’s disease, which the researchers proposed indicated that the premotor phase of the disease starts later in life.
One interpretation of this finding is that creative people are less likely to develop Parkinson’s disease. An alternative theory, however, may be that artist jobs are associated with a less stressful, more relaxed lifestyle.
Could it be that the lower levels of stress associated with artistic occupations may be having an impact on the risk of developing Parkinson’s disease?
This idea is not as crazy as it sounds.
Consider different kinds of stress. Research suggests that people who undergo tremendous emotional stress have a higher risk of developing Parkinson’s disease. For example, there is the case of ex-prisoners of war:
Title:Neurological disease in ex-Far-East prisoners of war
Authors: Gibberd FB, Simmonds JP.
Journal: Lancet. 1980 Jul 19;2(8186):135-7.
At the end of World war II, a neurological unit was set up at Queen Mary’s Hospital (Roehampton) to treat Ex-Far East prisoners of war. 4684 individuals were referred to the unit, of these 679 were found to have neurological disease (most of these – 593 cases – were loss of sight and peripheral nerve damage).
In follow up work in the 1970s, however, it was found that many of these individuals had gone on to develop other neurological conditions (dementia, multiple sclerosis, etc). Of interest to us, though was the finding that across the entire group of ex-prisoners investigated (4684 individuals), Parkinson’s disease was apparent in 24 of them – this is a frequency 5x that of the general population!
Even in animal models of Parkinson’s disease, emotional stress seems to exaccerbate the neurodegeneration that is being modelled:
Title: Stress accelerates neural degeneration and exaggerates motor symptoms in a rat model ofParkinson’s disease.
Authors: Smith LK, Jadavji NM, Colwell KL, Katrina Perehudoff S, Metz GA.
Journal: Eur J Neurosci. 2008 Apr;27(8):2133-46.
PMID: 18412632 (This article is OPEN ACCESS if you would like to read it)
The investigators in this study demonstrated that chronic stress exaggerates the motor/behavioural deficits in a rat model of Parkinson’s disease. In addition, the stress resulted in a greater loss of dopamine neurons in the brains of these rats.
For an interesting review of the effect of stress in Parkinson’s disease – Click here.
Interesting. So what did the Korean researchers – you mentioned above – find this week?
This is Dr Yoon-Il Lee.
He’s a dude.
He is a senior research scientists at the Daegu Gyeongbuk Institute of Science and Technology (DGIST) in Daegu Metropolitan City, South Korea.
Recently, his group has collaborated with Professor Yunjong Lee’s research team published this research report:
Title: Hydrocortisone-induced parkin prevents dopaminergic cell death via CREB pathway inParkinson’s disease model
Authors: Ham S, Lee YI, Jo M, Kim H, Kang H, Jo A, Lee GH, Mo YJ, Park SC, Lee YS, Shin JH, Lee Y.
Journal: Sci Rep. 2017 Apr 3;7(1):525. doi: 10.1038/s41598-017-00614-w.
PMID: 28366931 (This article is OPEN ACCESS if you would like to read it)
Dr Lee and his colleagues began this study with cells were engineered to produce a bioluminescent signal when a gene called Parkin was activated. Parkin is a Parkinson’s associated gene as genetic mutations in this gene can result in carriers developing a juvenile-onset/early-onset form of Parkinson’s disease.
The researchers then conducted an enormous screening experiment to find agents that turn on the Parkin gene. They applied a library of 1172 FDA-approved drugs (from Selleck Chemicals) to these cells – one drug per cell culture – and looked at which cell cultures began to produce a bioluminescent signal. They found 5 drugs that not only made the cells bioluminescent, but also resulted in Parkin protein being produced at levels 2-3 times higher than normal. Those drugs were:
- Deferasirox – an iron chelator (interesting considering our previous post)
- Vorinostat – a cancer drug (for treating lymphoma)
- Metformin – a diabetes medication
- Clindamycin – an antibiotic
Hydrocortisone produced the highest levels of Parkin (Interestingly, hydrocortisone also did not increase the activity of PERK, an indicator of endoplasmic reticulum stress, while the other drugs did).
What is Hydrocortisone?
Hydrocortisone is the name for the hormone ‘cortisol’ when supplied as a medication.
Ok, so what is cortisol?
Cortisol is a glucocorticoid (a type of hormone) produced from cholesterol by enzymes in the cortex of the adrenal gland, which sits on top of the kidneys. It is produced in response to stress (physical or emotional)
The location of the adrenal glands. Source: Cancer
Cortisol helps us to deal with physical or emotional stress by reducing the activity of certain bodily functions – such as the immune system – so that the body can focus all of it’s energies toward dealing with the stress at hand.
Now generally, the functions of cortisol are supposed to be short-lived – long enough for the body to deal with the offending stressor and then levels go back to normal. But the normal levels of cortisol also fluctuate across the span of the day, with levels peaking around 8-9am:
A graph of cortisol levels over the day. Source: HealthTap
Ok, so what did the Korean researchers do next?
Dr Lee and his colleagues gave the hydrocortisone drug to cell cultures which they then stressed (causing cell death). Hydrocortisone protected the cells from dying, and (importantly) it achieved this feat in a manner that was dependent on parkin activation. In cells that do not naturally have parkin, hydrocortisone was found to have no effect on cell survival.
Next the researchers treated mice with hydrocortisone before they then modelled Parkinson’s disease using the neurotoxin 6-OHDA. Hydrocortisone treatment resulted in approximate a two-fold increase in levels of parkin within particular areas of the brain. Without hydrocortisone treatment, the mice suffered the loss of approximately 45% of their dopamine neurons. Mice pre-treated with hydrocortisone, however, demonstrated enhanced dopamine neuron survival.
The researchers concluded that a sufficient physiological supply of hydrocortisone was required for protection of the brain, and that hydrocortisone treatment could be further tested as a means of maintaining high levels of parkin in the brain.
So what do we know about cortisol in Parkinson’s disease?
So this is where the story gets interesting;
Title: Cortisol is higher in parkinsonism and associated with gait deficit.
Authors: Charlett A, Dobbs RJ, Purkiss AG, Wright DJ, Peterson DW, Weller C, Dobbs SM.
Journal: Acta Neurol Scand. 1998 Feb;97(2):77-85.
The researchers who conducted this study were interested in the role of cortisol in Parkinson’s disease. They measured cortisol levels in the blood of 96 subjects with Parkinson’s disease and 170 control subjects. They found that cortisol levels were 20% higher in the subjects with Parkinson’s disease, and that MAO-B inhibitor treatment for Parkinson’s (Selegiline) reduced cortisol levels.
And MAO-B inhibitors are not the only Parkinson’s medication associated with reduced levels of cortisol:
Title: Acute levodopa administration reduces cortisol release in patients with Parkinson’s disease.
Authors: Müller T, Welnic J, Muhlack S.
Journal: J Neural Transm (Vienna). 2007 Mar;114(3):347-50.
In this study the researchers found that cortisol levels started to decrease significantly just 30 minutes after L-dopa was taken.
Whether this lowering of cortisol levels may have any kind of detrimental effect on Parkinson’s disease is yet to be determined and required further investigation.
Is hydrocortisone or cortisol used in the clinic?
Yes it is.
Hydrocortisone is used to treat rheumatism, skin diseases, and allergies.
Hydrocortisone tablets. Source: Wisegeeks
Thus, there is the potential for another example of drug repurposing here. But the drug is not without side effects, which include:
- Sleep problems (insomnia)
- Mood changes
- Acne, dry skin, thinning skin, bruising or discoloration;
- Slow wound healing
- Increased sweating
- Headache, dizziness, spinning sensation;
- nausea, stomach pain
For the full list of potential side effects – click here.
So what does it all mean?
Researchers in Korea have recently found that hydrocortisone (cortisol) can increase levels of Parkinson’s associated protein Parkin in cells, which in turn has a positive, neuroprotective effect on models of Parkinson’s disease.
We will now wait to see if the results can be independently replicated before attempting to take this drug to clinical trials for Parkinson’s disease. Any replication of the study should involve a range of treatment regimes so that we can determine if delayed administration can also be beneficial (this would involve delaying hydrocortisone treatment until after the neurotoxin has been given). Those studies could also look at the inflammatory effect in the brains as hydrocortisone has previously been demonstrated to have anti-inflammatory effects.
Interesting times. Stay tuned.
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. While some of the drugs discussed on this website are clinically available, they may have serious side effects. We urge caution and professional consultation before altering any treatment regime. SoPD can not be held responsible for any actions taken based on the information provided here.
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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.
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).
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.
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?
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:
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:
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:
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.
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.
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:
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 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”.
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.
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.
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.
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