Alpha Synuclein Structural Finding May Direct New Drug Development for Parkinson’s Disease

Clumps of proteins that accumulate in brain cells are a hallmark of neurological diseases such as dementia, Parkinson’s disease and Alzheimer’s disease. Over the past several years, there has been much controversy over the structure of one of those proteins, known as alpha synuclein. MIT computational scientists have now modeled the structure of that protein, most commonly associated with Parkinson’s, and found that it can take on either of two proposed structures— floppy or rigid. The findings suggest that forcing the protein to switch to the rigid structure, which does not aggregate, could offer a new way to treat Parkinson’s, says Dr. Collin Stultz, an associate professor of electrical engineering and computer science at MIT. “If alpha synuclein can really adopt this ordered structure that does not aggregate, you could imagine a drug-design strategy that stabilizes these ordered structures to prevent them from aggregating,” says Dr. Stultz, who is the senior author of a paper describing the findings that was published online on February 11, 2013 in an open-access article in the Journal of the American Chemical Society. For decades, scientists have believed that alpha synuclein, which forms clumps known as Lewy bodies in brain cells and other neurons, is inherently disordered and floppy. However, in 2011, Harvard University neurologist Dr. Dennis Selkoe and colleagues reported that after carefully extracting alpha synuclein from cells, they found it to have a very well-defined, folded structure. That surprising finding set off a scientific controversy. Some tried and failed to replicate the finding, but scientists at Brandeis University, led by Dr. Thomas Pochapsky and Dr. Gregory Petsko, also found folded (or ordered) structures in the alpha synuclein protein. Dr.
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