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?
Regular readers will be aware that here at the SoPD, we are on a mission to change the way we clinically test drugs (Click here for the most recent rant on this topic).
We have a lot of interesting drugs waiting in the pipeline to be clinically tested and an eager (read: desperate) population of individuals affected by Parkinson’s, but we are missing one critical part of the equation: better tools of assessment.
How can we determine whether a drug is actually working or not? And how can we better monitor people over time on said drug?
Our current methods assessing individuals with Parkinson’s rely heavily on clinical rating scales and brain imaging. These are basic tools at best, conducted episodically (annually in general, or once every 2-6 months during a clinical trial), and provide little in the way of useful objective data (on an individual basis).
In today’s post, we will look at a single aspect of Parkinson’s – sleep – and try to nut-out a better/more informative method of assessing it over time.
The Bluesky project. Source: Mirror
Last week tech industry giants Pfizer and IBM made an big announcement.
It was news that I have been quietly waiting to hear for some time.
It related to their “BlueSky Project” – a collaboration between the two companies to provide better methods of assessment/monitoring of Parkinson’s.
The two companies announced that they are now ready to start accepting the first participants for a new clinical trial.
And it is a really intriguing study for one simple reason:
The entire trial will take place inside one house.
On Saturday 7th January, 2018, one of the world’s largest pharmaceutical companies – Pfizer – announced that it was abandoning research efforts focused on finding new drugs for Alzheimer’s and Parkinson’s.
Naturally, the Parkinson’s and Alzheimer’s communities reacted with disappointment to the news, viewing it as a demoralising tragedy. And there was genuine concern that other pharmaceutical companies would follow suit in the wake of this decision.
Those fears, however, are unfounded.
In today’s post we will look at some of the reasons underlying Pfizer’s decision, why our approach to failure is wrong, why Pfizer will definitely be back, and what the Parkinson’s community can do about it all.
1. Our approach to failure
Matthew Syed. Source: Amazon
In the first chapter of his book, Syed makes comparisons between the way the aviation industry and the medical profession approach failure, pointing out the processes that follow situations when a disasters occur. In the aviation industry, when any event occurs there is a major investigative process that starts with the recovery of the black boxes. The aviation industry uses this system of investigation to learn from every single incident. It makes the information available to all and this helps with re-thinking everything from cockpit ergonomics and design to air traffic controller procedures. Even the airline companies are keen to be seen to be involved in this process of investigation. Failure, while unfortunate, is not shameful or stigmatising, but rather embraced and enlightening.
In addition, Syed points out that when an airline pilot sits down in his/her cockpit, their neck is also on the line if something goes wrong. Thus, it is in their best interest that the flight should be successful. And this is another reason why the aviation industry takes the reporting of failure so seriously. Everyone benefits from learning from previous situations. And all of this comes together with the observation that 2017 was the safest year on record for flying (based on deaths/flights – Source).
In Silicon valley (California), everyone is always looking for the “next killer app” – the piece of software (or application) that is going to change the world. The revolutionary next step that will solve all of our problems.
The title of today’s post is a play on the words ‘killer app’, but the ‘app’ part doesn’t refer to the word application. Rather it relates to the Alzheimer’s disease-related protein Amyloid Precursor Protein (or APP). Recently new research has been published suggesting that APP is interacting with a Parkinson’s disease-related protein called Leucine-rich repeat kinase 2 (or LRRK2).
The outcome of that interaction can have negative consequences though.
In today’s post we will discuss what is known about both proteins, what the new research suggests and what it could mean for Parkinson’s disease.
Seattle. Source: Thousandwonders
In the mid 1980’s James Leverenz and Mark Sumi of the University of Washington School of Medicine (Seattle) made a curious observation.
After noting the high number of people with Alzheimer’s disease that often displayed some of the clinical features of Parkinson’s disease, they decided to examined the postmortem brains of 40 people who had passed away with pathologically confirmed Alzheimer’s disease – that is, an analysis of their brains confirmed that they had Alzheimer’s.
What the two researchers found shocked them:
Title: Parkinson’s disease in patients with Alzheimer’s disease.
Authors: Leverenz J, Sumi SM.
Journal: Arch Neurol. 1986 Jul;43(7):662-4.
Of the 40 Alzheimer’s disease brains that they looked at nearly half of them (18 cases) had either dopamine cell loss or Lewy bodies – the characteristic features of Parkinsonian brain – in a region called the substantia nigra (where the dopamine neurons are located). They next went back and reviewed the clinical records of these cases and found that rigidity, with or without tremor, had been reported in 13 of those patients. According to their analysis 11 of those patients had the pathologic changes that warranted a diagnosis of Parkinson’s disease.
And the most surprising aspect of this research report: Almost all of the follow up studies, conducted by independent investigators found exactly the same thing!
It is now generally agreed by neuropathologists (the folks who analyse sections of brain for a living) that 20% to 50% of cases of Alzheimer’s disease have the characteristic round, cellular inclusions that we call Lewy bodies which are typically associated with Parkinson disease. In fact, in one analysis of 145 Alzheimer’s brains, 88 (that is 60%!) had chemically verified Lewy bodies (Click here to read more about that study).
A lewy body (brown with a black arrow) inside a cell. Source: Cure Dementia
Oh, and if you are wondering whether this is just a one way street, the answer is “No sir, this phenomenon works both ways”: the features of the Alzheimer’s brain (such as the clustering of a protein called beta-amyloid) are also found in many cases of pathologically confirmed Parkinson’s disease (Click here and here to read more about this).
So what are you saying? Alzheimer’s and Parkinson’s disease are the same thing???