Can a single protein help us to solve the mystery of Parkinson’s disease (PD)? The answer, scientists increasingly believe, may be yes. And the protein of interest? Identified more than two decades ago, it is alpha-synuclein (α-synuclein). In Parkinson’s disease, abnormal forms of this protein are found clumped together within dopamine neurons, the brain cells that help control smooth movement, as well as in other neurons.
The clumps, called Lewy bodies, are currently the only definitive confirmation we can get of a PD diagnosis, but they can only be seen at autopsy.
It turns out that Parkinson’s is not the only neurological disease to be identified with mysterious protein clumps in the brain. In both Alzheimer’s and Huntington’s diseases, for example, scientists have observed clumps of other proteins — known by the names beta-amyloid, tau, huntingtin and TDP-43 — in the brains of people who live with these conditions. And scientists have discovered that α-synuclein — the same protein that is found in PD — also clumps in a parkinsonism known as multiple system atrophy (MSA) and in dementia with Lewy bodies (DLB).
What can we learn from these clumps? Despite much research, it has been a challenge for scientists to understand normal α-synuclein and how it changes in Parkinson’s. But recent findings have cast new light on how the protein works and what its potential may be to help diagnose and treat the disease.
To find out more, we went to Dr. Dennis J. Selkoe, the Vincent and Stella Coates Professor of Neurologic Diseases at Harvard Medical School and Co-Director at the Center for Neurologic Diseases at Brigham and Women’s Hospital. As a neurological specialist, he cares for people with PD and DLB and conducts research with a special focus on α-synuclein. Together with colleague Tim Bartels, M.Sc., Ph.D., he has twice been awarded PDF funding to study the protein.
We sat down with Dr. Selkoe to talk about the mystery of α-synuclein and how science is coming closer to understanding its role. Here is what he told us.
Q. What is α-synuclein and why has it been linked to PD?
It is a naturally occurring protein that is found in all nerve cells of the body, as well as in red blood cells and other cells. Over the years, multiple discoveries from many scientific labs have greatly heightened interest in α-synuclein as a potential cause of PD. It has been linked to familial forms of PD (that is, mutations in the α-synuclein gene have been found to cause rare forms of inherited PD) and to genetic variants which increase risk for PD in the general population. It has also been shown to form clumps that are toxic to the dopamine neurons which are lost in PD. Moreover, the protein has been found to clump abnormally in two related diseases, dementia with Lewy bodies (DLB) and multiple system atrophy (MSA) — and even in some neurons in Alzheimer’s disease.
Q. How has our understanding of α-synuclein in PD changed over time?
In the 20 years or so since α-synuclein was discovered, there has been a major revision in our understanding of what normal α-synuclein looks like in the brain — that is, its structure and shape. For example, it was initially thought that strands of normal α-synuclein appeared alone, as individual molecules (monomers). Now it is known that normal α-synuclein is often folded into groups of four molecules, bound together in a natural cluster called a tetramer.
Research is helping scientists understand how the shape of α-synuclein in Parkinson’s might lead to the disease. The protein, when in groups of four (tetramers) can often protect itself from being damaged. But unfolded single strands (monomers) are at risk for damage that leads to clumping in Parkinson’s disease.
Q. How are these discoveries about the structure of α-synuclein helping us to better understand PD?
Our understanding of the size and shape of normal α-synuclein is helping us to understand what might go wrong in PD. For example, when studying α-synuclein tetramers, we found that there was strength in numbers — meaning their grouping into sets of four molecules allowed them to avoid the harmful aggregation (clumping) process that leads to PD. In other words, the tetramers resist the pressure to transform into toxic abnormal clumps. In contrast, excess α-synuclein monomers are known to promote the PD process — meaning they are much more likely than the normal tetramers to transform into the abnormal clumps, or aggregates, that prove toxic in PD.
We have seen this to be true for the rare genetic mutations in α-synuclein that cause PD. These mutations decrease the formation of healthy tetramers, which leaves more free monomers in the neuron. We believe that when this happens, it could trigger the transformation of normally shaped α-synuclein into the abnormal, unhealthy type.
Q. Could these findings point us toward newer or better therapies for PD?
In the future,research into α-synuclein will likely help us to develop drugs and antibodies that can stabilize healthy α-synuclein or help clear unhealthy forms from the brain, thus slowing down the loss of dopamine and other neurons in PD.
For example, we see potential in the concept of keeping α-synuclein in its healthy tetramer shape. In theory, if the protein remains as a tetramer, it may be safe from the process that leads to PD. But first, we have to find a way of stopping the tetramers from breaking up into monomers.
To accomplish this, we are screening existing drugs to find compounds that could help normal tetramers stay together and retain their shape, thereby avoiding the abnormal clumping of monomers that occurs in PD. We think that this might present an entirely new way of preventing the onset of PD and the related diseases, DLB and MSA. In all cases, we want to keep α-synuclein in its principal normal form (tetramers) and keep the level of the aggregation-prone monomers relatively low.
Currently, we rely on a doctor’s observation for a PD diagnosis. Could research on α-synuclein lead to better diagnostic tools for PD?
Yes, research could one day help scientists to routinely measure normal and abnormal forms of α-synuclein in cerebrospinal fluid (the liquid that bathes the brain and spinal cord) and perhaps even in blood, thus serving as tools to diagnose PD.
We may also find ways to visualize abnormal clumps of α-synuclein to diagnose PD through brain imaging. To get there, we need to find compounds that can be used in specialized brain scans — that could be injected intravenously and go to the brain to bind to abnormal α-synuclein aggregates. This would give us a way to detect the presence of Lewy bodies in cases of PD, DLB or MSA, both before and during the development of clinical symptoms of these diseases.
Q. When can people with PD expect treatments to be available that might “clear” the brain of too much α-synuclein?
This goal is now at the forefront of PD research. The approach involves addressing the problem of abnormal protein deposition — a crucial early step in the development of several degenerative brain diseases. Our goal in PD is analogous to worldwide efforts to prevent or slow the abnormal accumulation of the beta- amyloid protein as a treatment for Alzheimer’s disease.
As of today, there is no approved treatment that can prevent abnormal α-synuclein build-up or clear it from the brain. The good news is that there are now clinical trials afoot that are intended to do just that — to treat the build-up of the protein (e.g., with antibodies to α-synuclein that can be injected intravenously once a month). This development could present new hope for people who live with Parkinson’s disease.
Conclusion
For years, α-synuclein has been under intense investigation. While the protein remains somewhat mysterious, recent breakthroughs — about its size, shape and ability to spread in the brain — have allowed us insights into how it occurs normally — and what goes awry in PD.
Such discoveries are absolutely necessary for us to identify ways to more effectively diagnose, treat and perhaps one day prevent Parkinson’s disease.
Reviewed by Dr. Selkoe’s .
http://www.healthfeeds.co/2016/02/07/could-this-small-protein-hold-important-clues-for-solving-pd-unraveling-the-mystery-of-alpha-synuclein-at-drug-rehab-center/
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