Protein simulation, experiments unveil clues on origins of Parkinson's disease
Parkinson’s disease is the second most common neurodegenerative disease and affects more than 10 million people around the world. To better understand the origins of the disease, researchers from Penn State College of Medicine and The Hebrew University of Jerusalem have developed an integrative approach, combining experimental and computational methods, to understand how individual proteins may form harmful aggregates, or groupings, that are known to contribute to the development of the disease. They said their findings could guide the development of new therapeutics to delay or even halt the progression of neurodegenerative diseases.
Alpha-synuclein is a protein that helps regulate the release of neurotransmitters in the brain and is found in neurons. It exists as a single unit, but commonly joins together with other units to perform cellular functions. When too many units combine, it can lead to the formation of Lewy bodies, which are associated with neurodegenerative diseases like Parkinson’s Disease and dementia.
Although researchers know that aggregates of this protein cause disease, how they form is not well understood. Alpha-synuclein is highly disordered, meaning it exists as an ensemble of different conformations, or shapes, rather than a well-folded 3D structure. This characteristic makes the protein difficult to study using standard laboratory techniques — but the research team used computers together with leading-edge experiments to predict and study the different conformations it may fold into.
“Computational biology allows us to study how forces within and outside of a protein may act on it,” said Nikolay Dokholyan, professor of pharmacology at the College of Medicine and Penn State Cancer Institute researcher. “Using experiments performed in professor Eitan Lerner’s laboratory at the Biological Chemistry Department at The Hebrew University of Jerusalem, a series of algorithms accounts for effective forces acting in and upon a specific protein and can identify the various conformations it will take based on those forces. This allows us to study the conformations of alpha-synuclein in a way that is otherwise difficult to identify in experimental studies alone.”
This research was supported by the Michael J. Fox Foundation, National Institutes of Health, the Passan Foundation, the Israel Science Foundation, the Milner Fund and the Hebrew University of Jerusalem. This work was also supported by the National Center for Advancing Translational Science through Penn State Clinical and Translational Science Institute (grant UL1 TR002014). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or other funders.