The clustering (or aggregation) of the protein, alpha synuclein, is a cardinal feature of the Parkinsonian brain, and it is believed to be associated with the neurodegeneration that characterises the condition.
As a result, many pharmaceutical and biotech companies are focused a great deal of attention on identifying novel compounds that can enter the brain and inhibit alpha synuclein from aggregating. Recently, a collaboration of companies published the results of an amazingly large study highlighting novel inhibitors.
But an interesting aspect of the results was the ‘positive control’ compound they used: Epigallocatechin Gallate (or simply EGCG)
In today’s post, we will review the results of the study, discuss what EGCG is, and look at what is known about this compound in the context of Parkinson’s.
Every now and then, the research report of a huge study comes along.
And by that, I don’t mean that the results have a major impact. Rather, I am referring to the scope and scale of the work effort required to conduct the study. For example, the GIANT study which is looking for genetic variations associated with height (Click here to read a previous SoPD post that briefly touches on that study).
Recently, the report of one huge study was published:
Title: Potent α-Synuclein Aggregation Inhibitors, Identified by High-Throughput Screening, Mainly Target the Monomeric State
Authors: Kurnik M, Sahin C, Andersen CB, Lorenzen N, Giehm L, Mohammad-Beigi H, Jessen CM, Pedersen JS, Christiansen G, Petersen SV, Staal R, Krishnamurthy G, Pitts K, Reinhart PH, Mulder FAA, Mente S, Hirst WD, Otzen DE.
Journal: Cell Chem Biol. 2018 Aug 29. pii: S2451-9456(18)30271-X.
In this study, researchers from Arrhus University, Biogen, Amgen, Genentech, Forma Therapeutics, & Alentis Pharma screened almost 750,000 different compounds for their ability to interact with the Parkinsons-associated protein alpha synuclein.
And before we go any further, just take a moment to fully appreciate the size of that number again:
That is eye watering stuff! That is a “I need to sit down for a moment and let this sink in” kind of number. That is a “Are there that many compounds in all of the known universe?” number.
After reading the number, I was left wondering what each of the scientists involved in this study must have been thinking when the boss first said “Hey guys, let’s screen half a million compounds…. no, wait, better yet, why stop there. Let’s make it 3/4 of a million compounds”
How enthusiastic was the “Yes boss” response, I wonder?
All kidding aside, this is an amazing study (and the actual number of compounds screened was only 746,000).
And the researchers who conducted the study should be congratulated on their achievement, as the results of their study may have a profound impact in the longer-term for the Parkinson’s community – you see, the researchers found 58 compounds that markedly inhibited the aggregation of alpha synuclein, as well as another 100 compounds that actually increased its aggregation. A great deal of research will result from this single, remarkable piece of work.
But of particular interest to us here at the SoPD, was the activity of one of the positive control compounds that the researchers used in some of the tests.
What was the control compound?
This is one of those posts that I am reluctant to write because there is the very real possibility of it being taken out of context and causing someone to panic. But several readers have asked me to address a new piece of research that was published this week which has them concerned.
Anaesthetics are very useful agents in medicine, but they have long been known to have biological effects beyond simply numbing/sedating individuals. Some of those effects are beneficial, while others….mmm, not so beneficial. And the new research published this week leans towards the latter: Certain anaesthetics apparently induce mutant protein aggregation in neurons and cause stress responses in those brain cells.
In today’s post, we will discuss what anaesthetics are, how (we think) they work, and what the results of this new research actually mean.
William Morton’s first public demonstration. Source: Pinterest
On Friday 16th October 1846, history was made.
On that date, an American dentist named William T. G. Morton (1819-1868) made the first public demonstration of the use of inhaled ether as a surgical anaesthetic.
William Morton. Source: Wikipedia
At this demonstration Dr. John Collins Warren painlessly removed a tumor from the neck of a Mr. Edward Gilbert Abbott. After finishing the operation and Abbott had regained consciousness, Warren asked Abbott how he felt.
John Collins Warren. Source: General-anaesthesia
Abbott replied, “Feels as if my neck’s been scratched.”
Warren then turned to the medical audience and said:
“Gentlemen, this is no Humbug”
This was an obvious shot at an unsuccessful demonstration of nitrous oxide as a anaesthesia the year before (by Horace Wells in the same theatre), which ended with the audience shouting “Humbug!” after they heard the patient groaning with pain during the procedure.
The important thing to appreciate here is the magnitude of Morton’s achievement within in the history of medicine.
Before 16th October 1846, surgical procedures were not very pleasant affairs.
After 16th October 1846,… well, to be honest, they are still not very pleasant affairs, but at least the patient can skip most of the painful parts of an operation.
Interesting. But what does this have to do with Parkinson’s?
On this website, we regularly talk about a Parkinson’s-associated protein called Alpha Synuclein.
It is widely considered to be ‘public enemy #1’ in the world of Parkinson’s research, or at the very least one of the major ‘trouble makers’. It is a curious little protein – one of the most abundant proteins in your brain.
But did you know that there are different ‘species’ of alpha synuclein?
And recently researchers in Florida announced that they had identified an all new species of alpha synuclein that they have called “P-alpha-syn-star” or Pα-syn*.
In today’s post, we will discuss what is meant by the word ‘species’, look at the different species of alpha synuclein, and explore what this new species could mean for the Parkinson’s community.
This microscopic creature is called Macrobiotus shonaicus.
Isn’t it cute?
The researchers that discovered it found it in a Japanese parking lot.
It is one of the newest species of life discovered to date (Click here for the research report). It is a species of Tardigrade (meaning “slow stepper”; also known as a water bear or moss piglet). And for the uninitiated: Tardigrade are remarkable creatures.
Tardigrade. Source: BBC
They measure just 0.5 mm (0.02 in) long, there are approximately 1,150 known species of them, and they have been around for a VERY long time – with fossil records dating back to the Cambrian period (500 million years ago).
The tree of life (try and find the dinosaurs). Source: Evogeneao
But most importantly, tardigrade are EXTREMELY resilient:
- they are the first known animals to survive in hard vacuum and UV radiation of outer space. Some of them can withstand extreme cold – down to temperatures of −458 °F (−272 °C), while other species of Tardigrade can withstand extremely hot temperatures – up to 300 °F (150 °C) (Click here to read more)
- they can withstand 1,000 times more radiation than other animals (Click here for more on that)
- some species of Tardigrade can also withstand pressure of 6,000 atmospheres (that is nearly SIX times the pressure of water in the deepest ocean trench – the Mariana trench! Click here for more on this)
- They are one of the few groups of species that are capable of suspending their metabolism; surviving for more than 30 years at −20 °C (−4 °F – Click here to read about this)
They are utterly remarkable creatures.
Great, but what does this have to do with Parkinson’s? Continue reading
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.
We have previously written about the benefits of drinking coffee in reducing one’s chances of developing Parkinson’s disease (Click here for that post). Today, however, we shift our attention to another popular beverage: Tea.
Green tea in particular. Why? Because of a secret ingredient called Epigallocatechin Gallate (or EGCG).
Today’s post will discuss why EGCG may be of great importance to Parkinson’s disease.
Anyone fancy a cuppa? Source: Expertrain
INTERESTING FACT: after water, tea is the most widely consumed drink in the world.
In the United Kingdom only, over 165 million cups of tea were drunk per day in 2014 – that’s a staggering 62 billion cups per year. Globally 70 per cent of the world’s population (over the age of 10) drank a cup of tea yesterday.
Tea is derived from cured leaves of the Camellia sinensis, an evergreen shrub native to Asia.
The leaves of Camellia sinensis. Source: Wikipedia
There are two major varieties of Camellia sinensis: sinensis (which is used for Chinese teas) and assamica (used in Indian Assam teas). All versions of tea (White tea, yellow tea, green tea, etc) can be made from either variety, the difference is in the processing of the leaves.
The processing of different teas. Source: Wikipedia
There are at least six different types of tea based on the way the leaves are processed:
- White: wilted and unoxidized;
- Yellow: unwilted and unoxidized but allowed to yellow;
- Green: unwilted and unoxidized;
- Oolong: wilted, bruised, and partially oxidized;
- Black: wilted, sometimes crushed, and fully oxidized; (called “red tea” in Chinese culture);
- Post-fermented: green tea that has been allowed to ferment/compost (“black tea” in Chinese culture).
More than 75% of all tea produced in this world is considered black tea, 20% is green tea, and the rest is made up of white, Oolong and yellow tea.
What is the difference between Green tea and Black tea?
Green tea is made from Camellia sinensis leaves that are largely unwilted and heated through steaming (Japanese style) or pan-firing (Chinese style), which halts oxidation so the leaves retain their color and fresh flavor. Black tea leaves, on the other hand, are harvested, wilted and allowed to oxidize before being dried. The oxidation process causes the leaves to turn progressively darker.
So what does green tea have to do with Parkinson’s disease?
In 2006,this research paper was published:
Title: Small molecule inhibitors of alpha-synuclein filament assembly
Authors: Masuda M, Suzuki N, Taniguchi S, Oikawa T, Nonaka T, Iwatsubo T, Hisanaga S, Goedert M, Hasegawa M.
Journal: Biochemistry. 2006 May 16;45(19):6085-94.
In this study, the researchers tested 79 different chemical compounds for their ability to inhibit the assembly of alpha-synuclein into fibrils. They found several compounds of interest, but one of them in particular stood out: Epigallocatechin Gallate or EGCG
The chemical structure of EGCG. Source: GooglePatents
Now, before we delve into what exactly EGCG is, let’s take a step back and look at what is meant by the “assembly of alpha-synuclein into fibrils” (???).
We have previously written a lot about alpha synuclein (click here for our primer page). It is a protein that has been closely associated with Parkinson’s disease for some time now. People with mutations in the alpha synuclein gene are more vulnerable to developing Parkinson’s disease, and the alpha synuclein protein is found in the dense circular clumps called Lewy bodies that are found in the brains of people with Parkinson’s disease.
A lewy body (brown with a black arrow) inside a cell. Source: Cure Dementia
What role alpha synuclein plays in Parkinson’s disease and how it ends up in Lewy bodies is the subject of much research and debate. Many researchers, however, believe that it all depends on how alpha synuclein ‘folds’.
The misfolding of alpha synuclein
When a protein is produced (by stringing together amino acids in a specific order set out by RNA), it will then be folded into a functional shape that do a particular job.
Alpha synuclein is slightly different in this respect. It is normally referred as a ‘natively unfolded protein’, in that is does not have a defined structure. Alone, it will look like this:
Alpha synuclein. Source: Wikipedia
By itself, alpha synuclein is considered a monomer, or a single molecule that will bind to other molecules to form an oligomer (a collection of a certain number of monomers in a specific structure). In Parkinson’s disease, alpha-synuclein also aggregates to form what are called ‘fibrils’.
Microscopic images of Monomers, oligomers and fibrils. Source: Brain
Oligomer versions of alpha-synuclein are emerging as having a key role in Parkinson’s disease. They lead to the generation of fibrils and may cause damage by themselves.
It is believed that the oligomer versions of alpha-synuclein is being passed between cells – and this is how the disease may be progressing – and forming Lewy bodies in each cells as the condition spreads.
For this reason, researchers have been looking for agents that can block the production of alpha synuclein fibrils and stabilize monomers of alpha synuclein.
And now we can return to EGCG.
What is EGCG?
Epigallocatechin Gallate is a powerful antioxidant. It has been associated with positive effects in the treatment of cancers (Click here for more on that).
And as the study mentioned near the top of this blog suggested, EGCG is also remarkably good at blocking the production of alpha synuclein fibrils and stabilizing monomers of alpha synuclein. If the alpha synuclein theory of Parkinson’s disease is correct, then EGCG could be the perfect treatment.
EGCG blocks the formation of oligomers. Source: Essays in Biochemistry
And there have been many studies replicating this effect:
Title: EGCG remodels mature alpha-synuclein and amyloid-beta fibrils and reduces cellular toxicity
Authors: Bieschke J, Russ J, Friedrich RP, Ehrnhoefer DE, Wobst H, Neugebauer K, Wanker EE.
Journal: Proc Natl Acad Sci U S A. 2010 Apr 27;107(17):7710-5. doi: 10.1073/pnas.0910723107.
PMID: 20385841 (This article is OPEN ACCESS if you would like to read it)
In this particular study, the researchers found that EGCG has the ability to not only block the formation of of alpha synuclein fibrils and stabilize monomers of alpha synuclein, but it can also bind to alpha synuclein fibrils and restructure them into the safe form of aggregated monomers.
And again, what has Green tea got to do with Parkinson’s disease?
Green tea is FULL of EGCG.
In the production of Green tea, the picked leaves are not fermented, and as a result they do not go through the process of oxidation that black tea undergoes. This leaves green tea extremely rich in the EGCG, and black tea almost completely void of EGCG. Green tea is also superior to black tea in the quality and quantity of other antioxidants.
What clinical studies have been done on EGCG and Parkinson’s disease?
Two large studies have looked at whether tea drinking can lower the risk of Parkinson’s disease. Both studies found that black tea is associated with a reduced risk of Parkinson’s disease, but one of the studies found that drinking green tea had no effect (Click here and here for more on this). Now the positive effect of black tea is believed to be associated with the high level of caffeine, which is a confounding variable in these studies. Even Green tea has some caffeine in it – approximately half the levels of caffeine compared to black tea.
The levels of EGCG in these studies were not determined and we are yet to see a proper clinical trial of EGCG in Parkinson’s disease. EGCG has been clinically tested in humans (Click here for more on that), so it seems to be safe. And there is an uncompleted clinical trial of EGCG in Huntington’s disease (Click here for more) which we will be curious to see the results of.
So what does it all mean?
It means that if the alpha-synuclein theory of Parkinson’s disease is correct, then more research should be done on EGCG. Specifically a double-blind clinical trial looking at the efficacy of this antioxidant in slowing down the condition.
It means that I now drink a lot of green tea.
It’s very nice. Have a try.
The banner for today’s post was sourced from WeightLossExperts