Protein Aggregation, Story Telling, and the Search for Truth – A Tale of Science and Society

(The following was reviewed and edited by Prof. Alberto J. Espay and is based on his paper in Neurology released today, February 12^th, 2019) 

 

Have you heard the joke about the drunk looking for his keys? If not it goes like this…

“A policeman sees a drunk man searching for something under a streetlight and asks what the drunk has lost. He says he lost his keys and they both look under the streetlight together. After a few minutes the policeman asks if he is sure he lost them here, and the drunk replies, no, and that he lost them in the park. The policeman asks why he is searching here, and the drunk replies, “this is where the light is” – (wiki)

It has been told to me a couple times on this journey I’ve been on trying to make sense of Parkinson’s disease, and the further I go the more it seems to ring true.

 

Early on I learned that the field is largely driven by a belief that this disease can be explained by the misfolding of a single protein, alpha-synuclein, into Lewy bodies (clumps of proteins, the presence of which, upon autopsy, is necessary to confirm the clinical diagnosis of Parkinson’s). So, stop aggregation and we’ll stop the disease. This was very comforting, a nice tidy explanation with a clear target. I dug a little deeper and saw that the evidence was pretty compelling. For one, families with a rare duplication or triplication of the alpha-synuclein gene have drastically higher rates of the disease. And two, autopsies revealed that the vast majority of people who have died with Parkinson’s had these proteins aggregating in their brains. These pieces of evidence were enough to label alpha-synuclein ‘pathogenic’, meaning the cause of disease.

This is a picture taken in Lausanne, Switzerland at a meeting called the Synuclein Conference. Every year these experts come together to discuss all the latest science has to say about this protein. (The conference was noteworthy for more than just the science discussed, click here to read my notes from the conference)

I was lucky enough to get invited this past year when, for three days, I sat and listened to all that we know, and all that we don’t know, about alpha-synuclein. The organizers of the event, particularly Prof. Hilal Lashuel, had done a marvelous job of setting the tone for open and free discussions, enabling the presentation of unpublished data as well as healthy debates about how to move forward. This was science as it should be.

But, there was a question that lingered in my head throughout the meeting. Towards the end I stood up and asked the room, “what is our best evidence that these protein accumulations might be an effect of having Parkinson’s rather than a cause?” There was some turning of heads and some muffled comments before one of the speakers on stage at the time noted that there are some people with the disease that carry specific genetic mutations (in genes named PINK1 and Parkin) who upon autopsy were revealed to not have these protein clumps. With that the room seemed satisfied and the conference proceeded with the regularly scheduled programming.

But, how could it be that those with PINK1 and Parkin mutations don’t have these clumps yet still have Parkinson’s? After all, the field has made it pretty clear that these protein accumulations are the fundamental signature of what is called “Parkinson’s disease”.

I looked and looked but found no convincing explanations for this contradiction. Then I saw this…

 

 

In this paper published today in Neurology, Alberto J. Espay and colleagues present what seems to be the most convincing case yet that these protein clumps may not be a cause of Parkinson’s disease. They also present some alternative hypothesis that may explain the relationship between Parkinson’s and alpha-Synuclein, as well as how we should move forward with this new understanding in mind.

I won’t go into the details, it is all there in the paper (though it is important to read and understand them), but I did want to point out that if what is proposed is correct then it is hard to understate the implications. Billions of dollars and countless hours of work are being spent on the assumption that these protein aggregates are pathogenic. Almost all of our models of this disease just model this aggregation, and there are a great number of ongoing trials that were justified on the basis that they target these same aggregates. It may not be hyperbole to say that all those models need to be discarded, and all those trials stopped.

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For most of my life I was a passive consumer of science. I’d occasionally read a few articles and popular science books and generally took as gospel most of what was acknowledged to be scientific consensus. From the outside science looks like the ultimate storehouse of credibility from which all that we know about the world emerges fully formed. However, for the last few years I have had the distinct pleasure of entering that house and getting to browse the section labeled ‘Neurology and Neuroscience – Subsection: Parkinsonisms’. At first glance it appeared relatively neat and tidy, but having now read through many of its volumes (and even having met most of its living authors and authored a few pages myself), I see that it is in need of critical review and that many of those volumes have been filled by a narrative we created around misfolded proteins that is driving most of our attempts to understand and treat this disease.

I want to make clear that I do not say this to denigrate the work done. The study of the brain is hard. I often equate what the field is trying to do today in combating these diseases to attempts to build rocket ships in the early 19^th century: the knowledge and tools just aren’t there yet.

It’s also important to emphasize that science is a man-made system we created to understand the world. In it evidence and theory mix to become belief, over time beliefs get tested, some get whittled away, others garner further evidence. With enough time, those beliefs spread through society and become hardwired into our culture.

But the beauty of science is that, like the very biology that gave rise to us, it is self-correcting. At some point an alternative hypothesis emerges that is convincing enough to be worthy of further testing. The question then becomes, how much of our resources should we spend continuing to follow the breadcrumbs that led us to where to we are today until we have exhausted all possibilities, and how much should we spend pivoting towards the start of a new trail that would lead us in a completely different direction?

This is the question the field faces today. There are ten ongoing trials in various stages of clinical development that directly target alpha-synuclein, and many more in preclinical development. The majority of experts in the field believe this target represents our best chance for modifying the course of this disease. Yet, I cannot help but look at the number of trials in Alzheimer’s disease (where protein accumulation is also at the center of how that disease is defined) that have consistently fallen short and wonder, is the field of Parkinson’s disease now repeating the mistakes of science past?

These are not easy questions for anyone to answer, every step has lives on the line, and the clock is ticking. I have never had to make these decisions myself, I do not know what that responsibility is like, but for what it is worth, I think the evidence we have accumulated to date, and the reasoning put forth by Espay and colleagues, is sufficient enough that we should now devote more of our attention and resources towards looking elsewhere for the keys to this puzzle. Perhaps, as the field has paradoxically been implying for over a decade now, there is no single key and the best way forward is to take a step back and truly embrace what was meant by the words displayed at that very same Synuclein Conference in Lausanne…

“If you meet one person with Parkinson’s disease, you’ve met one person with Parkinson’s disease.”

 

(Click here to read the paper from Prof. Alberto Espay and colleagues)

 

(Banner image: Drawing Hands is a lithograph by the Dutch artist M. C. Escher first printed in January 1948.)

 

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