Alpha synuclein is a protein that is closely associated with Parkinson’s. But exactly if and how it is connected to the neurodegenerative process underlying the condition, remains unclear.
Last week researchers reported that removing a particular form of alpha synuclein in mice results in a very early onset appearance of characteristics that closely resemble the features of Parkinson’s that we observe in humans. This finding has caused some excitement in the research community, as not only does this tell us more about the alpha synuclein protein, but it may also provide us with a useful, more disease-relevant mouse model for testing therapies.
In today’s post, we will discuss what alpha synuclein is, explain which form of the protein was disrupted in this mouse model, review the results of the new study, and look at how tetramer stablising drugs could be a new area of PD therapeutics.
The 337 metre (1,106 ft) long USS Gerald R. Ford. Source: Wikipedia
Imagine you and I are standing in front of the world’s largest aircraft carrier, the USS Gerald R. Ford.
It is a VAST warship – measuring in at 337 metres (1,106 ft) in length, 76 metres (250 feet) in height – and it is a wonder of engineering composed of over a billion individual components.
And as we are standing there, gazing up at this amazing machine, I turn to you and put a nut & bolt into the palm of your hand.
A nut and bolt. Source: Atechleader
You look down at it for a moment, then turn to me, puzzled.
And that is when I say: “I would like you to find (without aid/instructions) where on this ship versions of this particular type of nut and bolt live, and try to determine exactly what functions they have“.
Where would you even start?
What tools would you use for the job? Considering the size and complexity of the vessel, would you simply give up before even starting?
It sounds like a ridiculously daunting task, but this is in effect what neurobiologists are trying to do with their study of the brain. They start with a protein – one of the functional pieces of machinery inside each cell of our body – and then try to determine where in the brain it lives (the easy part) and what it does exactly (the REALLY hard part – most proteins have multiple functions and different configurations).
A good example of this is the Parkinson’s-associated protein alpha synuclein:
Alpha synuclein. Source: Wikipedia
Alpha synuclein is one of the most abundant proteins in our brains – making up about 1% of all the proteins floating around in each neuron in your head – and it is a very well studied protein (with over 9700 research reports listed on the Pubmed search engine with the key words ‘alpha synuclein’).
But here’s the thing: we are not entirely clear on what alpha synuclein actually does inside the cell.
In fact, biologists are not even sure about what the ‘native’ form of alpha synuclein is!
What do you mean?
An important aspect of developing new potentially ‘curative’ treatments for Parkinson’s is our ability to accurately test and evaluate them.
Current methods of assessing Parkinson’s are basic at best (UPDRS and brain imaging), and if we do not improve our ability to measure Parkinson’s, many of those novel treatments will fail the clinical trial process and forever remain just “potentially” curative.
Glasses are a wearable device that the majority of us take for granted. But two technology companies have announced that they are partnering up to focus their combined efforts on making a pair of glasses that could help improve the lives of people with Parkinson’s.
One company focuses on tracking facial expressions, while the other analyses audio.
In today’s post, we will look at how these technologies could be applied to Parkinson’s, and discuss what the companies have planned.
Looking good. Source: 1zoom
An interesting fact:
Approximately 60% of western populations wear glasses, contact lenses or use some other reading/visual aid (Source). And as we age, this percentage only increases – with the over 75 year olds representing a solid collection within the bespectacled crowd (see graph below).
More women than men wear glasses. Source: CBS
I am in the majority.
But mostly for aesthetic reasons (they make me look smarter than I actually am).
Ok, but what does this have to do with Parkinson’s?
During the last week of September, the Van Andel institute and the Cure Parkinson’s Trust held their annual Parkinson’s research meetings in Grand Rapids, Michigan.
The meetings – the Linked Clinical Trials meeting, Grand Challenges in Parkinson’s, and Rallying to the Challenge – provided an opportunity for members of the Parkinson’s community (both researchers and advocates) to come together, share research/knowledge/experience, and discuss what needs to be done.
I attended the meetings this year for the first time.
In today’s post, I thought I would provide some feedback and share some of my thoughts on the meetings.
Jay Van Andel (left) and Rich DeVos. Source: Amwayconnections
The history of Amway is an interesting story.
One of ambition, determination, and a refusal to give up.
It begins with the two founders – Jay Van Andel and Rich DeVos – trying and failing to get seven different businesses off the ground before they eventually founded the multi-level marketing company that we know of as Amway.
One aspect of the story that many people do not know, however, is that for a decade before he passed away in 2004, Jay Van Andel lived with Parkinson’s.
Determining exactly how many individuals there are in the world that are affected by Parkinson’s is a difficult task. Previously, a lot of ‘gues-stimation’ has been used in these quantitative efforts. But a clearer idea of the geographical, national and regional spread of Parkinson’s burden, could provide us with very useful information to help better understand the condition.
The Global Burden Disease Collaborators conducted a world-wide assessment of Parkinson’s burden in 2016, and this week the results of their study were published. The findings make for interesting reading.
In today’s post, we will review the results and discuss what they mean for the Parkinson’s community.
This is one of those classic ‘boy meets girl’ stories… but with a ‘saves the world’-kind of twist to it.
Having just graduated from Duke University (with a degree in computer science and economics) in the summer of 1986, Melinda Ann French began working as an intern for IBM. Having learnt to program (in Basic) on Apple II computers during her teens, she was interested in a future career in the developing world of computer technology.
She eventually scored a job with a new company called Microsoft, and for the next 6 years she climbed the corporate ladder, from a software marketing position to general manager of information products (such as Microsoft Bob, Expedia, and Encarta).
Melinda met William (Bill) Henry Gates III four months after starting her job at Microsoft – they happened to sit next to each other at a trade-fair dinner in New York. But several months would pass by before Bill actually asked her out on a date.
They were married in Hawaii on New Years day 1994.
In 2000, the couple launched the Bill and Melinda Gates Foundation – which has gone on to become one of the largest private foundations in the world with US$50+ billion in assets.
Excuse me, this is all very interesting, but what does it have to do with Parkinson’s?
At the end of each month the SoPD writes a post which provides an overview of some of the major pieces of Parkinson’s-related research that were made available during September 2018.
The post is divided into five parts based on the type of research (Basic biology, disease mechanism, clinical research, other news, and Review articles/videos).
So, what happened during September 2018?
In world news:
September 2nd – A fire destroyed the National Museum of Brazil in Rio de Janeiro – a “catastrophic loss of artifacts”.
September 14th – Hurricane Florence made landfall in Wrightsville Beach (North Carolina), caused extensive damage and flooding throughout in the Carolinas.
September 17th – In an effort to study the hidden physical properties of electrons, Japanese researchers built the ‘most powerful magnet on Earth’ – a 1200 Tesla, 3.2 megajoules beast. The experiment was supposed to go off with a bang, but the ‘bang’ was slightly more than expected: it blew the door off the protective chamber holding the experiment!
September 21st – after a three year journey, the first rover of the Japanese Hayabusa2 spacecraft touched down on the surface of the asteroid Ryugu. A truly remarkable achievement.
Source: NYTimes (some amazing images on this link)
September 24th – Two reports were published – one in the journal Nature Medicine and another in the journal New England Journal of Medicine – describing the case of 29-year-old Jered Chinnock (who 5 years ago could not feel or move his body from the chest down) recovering the ability of assisted walking following spinal cord stimulation and intensive physical therapy.
September 28th – A magnitude 7.5 earthquake hit the island of Sulawesi (Indonesia), causing a tsunami and terrible destruction and loss of life.
In the world of Parkinson’s research, a great deal of new research and news was reported:
In September 2018, there were 841 research articles added to the Pubmed website with the tag word “Parkinson’s” attached (5978 for all of 2018 so far). In addition, there was a wave to news reports regarding various other bits of Parkinson’s research activity (clinical trials, etc).
The top 5 pieces of Parkinson’s news
In 2017, a research report suggested that people taking the asthma treatment Salbutamol had a lower risk of developing Parkinson’s. In addition, that same study suggested that another medication called Propranolol – which is used for hypertension/high blood pressure – increased ones risk of developing Parkinson’s.
Both drugs work via a molecule called the Beta2 adrenoreceptor. The study caused a lot of excitement, and clinical studies were even proposed.
Now, however, new research suggests that these associations may not actually exist and those clinical trial plans will be need to be put on standby.
In today’s post we will discuss what the Beta2 adrenoreceptor is, how these two drugs (Salbutamol and Propranolol) affect it, and look at what the new results suggest.
Saul Goodman. Source: Amc
There is a popular show on Netflix called ‘Better call Saul’ (the title of this post is a play on the name).
It chronicles the life of a lawyer – named Saul Goodman – who struggles to make his way in the grey world of the law profession. He fights to survive by taking the information he has, and using it to plead his cases. But sometimes the original pieces of information he is dealing with are not always what they appear to be.
A similar situation faces researchers the world over.
Every day new information is reported. And this process is unrelenting. It simply never stops.
For Parkinson’s research alone, every day there is about 20 new research reports (approximately 120 per week).
But determining what is ‘usable’ information relies on independent replication. And sometimes efforts to validate a new finding fail to reproduce the initially reported results.
An example of this has occurred recently in the world of Parkinson’s research, with some rather large implications.
For the purposes of transparency and full disclosure, there have been some changes in my personal circumstances that I need to make you aware of going forward.
No, the SoPD is not stopping (calm down Lionel), but it will no longer be the blog of a research scientist.
Let me explain:
In December of of 2017, the results of a clinical trial suggested that a particular kind of exercise may have beneficial effects against certain aspects of Parkinson’s. Specifically, a high-intensity treadmill regime was found to be ‘non-futile’ as an intervention for the motor symptoms in de novo (newly diagnosed) Parkinson’s.
Recently, however, new pre-clinical research has been published which reported that when mice with particular Parkinson’s-associated genetic mutations are exercised to exhaustion, they have high levels of inflammation which can exaggerate the neurodegeneration associated with that model of PD.
So naturally, some readers are now asking “So should I be exercising or not?!?”
In today’s post we will review the results of the two studies mentioned above, and discuss why exercise is still important for people with Parkinson’s.
Readers are recommended to click on the image above and listen to the music (Michael Sembello’s “Maniac” from 1983) whilst reading this post.
This song was made famous by one particular scene from the 1983 movie “Flashdance” starring Jennifer Beals, in which the lead character undertook an intense dance routine. Ever since that iconic scene, exercise fanatics have long used the music to help get themselves into the mood for their workouts.
One of my personal life goals. Source: Jobcrusher
Few experts would disagree that the benefits of exercise are many.
Adults who achieve at least 2.5 hours of physical activity per week have:
- up to a 35% lower risk of coronary heart disease and stroke
- up to a 50% lower risk of type 2 diabetes
- up to a 50% lower risk of colon cancer
- up to a 20% lower risk of breast cancer
- a 30% lower risk of early death
- up to an 83% lower risk of osteoarthritis
- up to a 68% lower risk of hip fracture
- a 30% lower risk of falls (among older adults)
- up to a 30% lower risk of depression
- up to a 30% lower risk of dementia
But what about people with PD? What do we know about exercise and Parkinson’s?
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 week a new research report was released that got a few readers concerned.
The article published in the journal Neuropsychopharmacology suggested that there may be an association between early onset Parkinson’s and Attention Deficit Hyperactivity Disorder (or ADHD).
In today’s post, we will discuss what ADHD is, look at what the results of the study are proposing, and we will try to calm some nerves by explaining that while the results are very interesting (if they can be replicated and validated in a larger data set), the association only affects a very small number of individuals.
Source: Huffington Post
It may come as a bit of a surprise, but one of the most popular pages on this website deals with Attention Deficit Hyperactivity Disorder (or ADHD – click here to read that post).
I am not sure why this is the case.
At the time of writing that particular post, there was very little in the way of any associations between Parkinson’s and ADHD. But this week the number of views for that ADHD post went through the roof.
This increase in activity probably had less to do with my amazing prose and more to do with the release of this research report:
Title: Increased risk of diseases of the basal ganglia and cerebellum in patients with a history of Attention-Deficit/Hyperactivity Disorder
Authors: Curtin K, Fleckenstein AE, Keeshin BR, Yurgelun-Todd DA, Renshaw PF, Smith KR, Hanson GR.
Journal: Neuropsychopharmacology. 2018 Sep 12.
For those who don’t have time to read on, here is the short version of what today’s post is going to say: the results of the study are interesting, but the observed association only affects a very small number of individuals. And until the results are replicated and validated in a much larger study, there is little reason to panic.
And now for the ridiculously long version of this post – let’s start with the obvious first question:
What is ADHD?