Futurism, Medicine, Parkinson's
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Interview With Protein Folding Expert Prof. Kelvin Luk

Kelvin C. Luk, PhD. is a research assistant professor of pathology and laboratory medicine at the University of Pennsylvania Perelman School of Medicine. His research aims to improve our understanding of the role of protein misfolding in Parkinson’s Disease. Histopathological, genetic, and experimental evidence suggest that the aggregation and accumulation of alpha-synuclein (α-Syn), the primary component of Lewy bodies, underlies the symptoms seen in PD. Prof. Luk’s lab previously demonstrated that aggregated forms of α-Syn are transmissible entities that propagate and spread throughout the brain in a manner akin to prion diseases. This exciting discovery represented a significant shift in our understanding of PD etiology and progression. Through the development of novel biophysical, cell-based and animal models, his work seeks to further identify factors that a) regulate α-Syn expression and misfolding, b) determine its route of transmission and c) modulate the toxicity of α-Syn pathology.


For a brief primer on protein folding watch this video from Science Magazine…

The following has been paraphrased from an interview with Prof. Kelvin Luk on February 9, 2018. 

(Click here for the full audio version)



Do you believe PD to primarily be a protein folding problem?

Yes and no, when I think of Parkinson’s disease the first thing that comes to mind are the patients as well as the symptoms and challenges they face. What actually got me interested in PD is seeing some friends and family members living with the condition. But at the heart of the disease, in terms of the mechanisms and the basic biology that underpins what’s happening, I do see it as a protein folding defect.

Do you believe that the factors that lead to the initial misfolding are also responsible for the formation of oligomers and fibrils (bigger clumps of misfolded proteins)?

Determining the source at which these proteins initially misfold is still a bit of a black box to researchers in the field. When I talk about protein misfolding I am generally referring to one specific protein, called alpha-synuclein (which is found in Lewy bodies), in either a fibril or oligomer form. We know that once this protein starts to misfold (that is to adopt an abnormal shape), it triggers a cascade of more misfolding of this protein. The cause for the initial misfolding is still a black box because we still know very little about the correct shape that alpha-synuclein should be in for it to function properly.

When you look upstream, at the factors that lead to misfolding, what do you see and do you believe it is feasible to try and tackle this problem further upstream?

Ideally we would want to tackle both. We often have a linear view of therapy and think there will be a silver bullet that can address these problems, but a combination of therapies may be more effective than individual therapies. In Parkinson’s that will likely be the case because the event that is responsible for the misfolding probably took place years ago, making it very difficult to target. But if we can identify that cause it will likely also be beneficial to try and inhibit it. One of the more creative approaches being tried right now is reducing alpha-synuclein expression overall using antisense oligonucleotides (which inactivate messenger RNA, effectively turning ‘off’ the target gene), and is an attempt to tackle the problem from both sides of the equation.

It seems when most people mention protein misfolding they talk about proteins that fold in on themselves and then aggregate with other proteins, but how much, if any, of the problem is the opposite, proteins that are too stiff and don’t fold enough?

Instead of thinking about the physical properties of proteins – how stiff it is or what shape it might be in – it is useful to think of it in terms of its function. Because proteins are very complicated structures, they need to fold into a specific shape to do their job, almost any other shape leads to loss of function of that protein. Also, some proteins fold in ways that still allow it to do its primary job but that gain functions which might make them toxic. We’re learning now that it’s not so much the flexibility or the shape but a loss or gain of function that can create problems.

Do you think the aggregates that lead to neurodegeneration do so by resulting in the death of the cell or do they just lead to loss of function and if we can clear them will cells be able to function again? (function, in the case of PD, would mean to produce dopamine again)

That is still an unsolved question that many researchers are trying to answer. We do know that these aggregates, in particular Lewy bodies, are associated with something detrimental. Almost all of our experimental data tells us that these aggregates tend to be bad for the cell. However, there are researchers who believe that by forming aggregates of these proteins our cells might actually be preventing something that’s even worse, so protein aggregation could actually be a defense mechanism. It’s speculation at this point, but nonetheless is plausible. We also don’t know yet if patient’s symptoms would actually improve if we managed to remove these aggregates. I can’t think of any examples where this has been done successfully, so we haven’t really been able to test this hypothesis properly yet.

How different are the different types of alpha-synuclein? How many different strains are there? Have we made any progress in determining which strains lead to which disease phenotypes (clinical symptoms)?

Different strains typically refer to variants of a disease causing agent that have characteristic disease properties. What we see is that there are several diseases  that are all characterized by having alpha-synuclein aggregates (for example, PD, Dementia with Lewy Bodies, Multiple Systems Atrophy), which is why these diseases are also called synucleinopathies. Clinically they are very different, and that has led to the idea that there might be multiple strains of alpha-synuclein. Since there are at least half-a-dozen different diseases that we call synucleinopathies, that might also mean that there are a similar number of strains. Also, in test tubes there are groups that have been able to generate at least half-a-dozen different strains with unique properties, though theoretically there could be hundreds of different strains.

Where do you fall in the prion debate and why does it matter if PD is classified a prion disease?

The word prion was originally used to describe infectious proteins that can be transmitted from organism to organism. Using that strict definition, PD is not a prion disease. In some ways alpha-synuclein does behave like a prion protein in that it can self-amplify (grow more of themselves), spread from one part of the body to another, and exist as multiple strains that cause disease. But what’s missing is the ability to spread between organisms or individuals. This has important implications since it would influence not only the way we treat the disease but would add an unfounded stigma around PD if people were to take this to mean it is an infectious disease.

Is life itself a protein folding problem?

In many ways it is, though I might not use the word “problem”. I believe it was the well-known biologist Susan Lindquist who likened life to a ‘dance of proteins’. They need to be in good shape, well coordinated, and if they are doing what they are supposed to then it is a very beautifully choreographed sequence of events that takes place. But when something goes wrong, or it gets out of balance, then it becomes a proverbial train wreck. Being able to balance and regulate proteins is a challenge, but it is also how organisms sustain life


For more on the role of protein folding in Neurodegenerative diseases watch the above video from the late Prof. Susan Lindquist.

1 Comment

  1. Excellent interview Ben – if I remember correctly, it was only a couple of years ago that A-SYN was actually seen for the first time inside healthy cells. These were not the mis-folded proteins found in PD, yet even then, it was basically a messy ball so that must have come as a bit of a shock!


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