Alpha-synuclein

Protein Structure and Parkinson’s Disease

α-synuclein

As health care and nutrition improve throughout the world, people are living longer. Strides are being made against the old killers (cancer, heart disease) that prevented most people from living into their seventies and eighties. But as the population ages, neurodegenerative diseases that disproportionately affect the elderly are becoming a public health crisis. For a short, entertaining and informative talk on this subject by our collaborator Greg Petsko, see the adjacent video.

Parkinson’s Disease (PD) and Alzheimer’s Disease (AD) decrease the quality of life for patients and put strains on families caring for elderly relatives and an already overburdened healthcare system. Except in rare cases where a particular genetic defect has been identified, we do not know what causes PD or AD. However, a hallmark of both diseases is the formation of precipitates of mis-folded proteins. In healthy cells, mechanisms exist for the identification and break-down of mis-folded or otherwise defective proteins. These mechanisms appear to break down or are overloaded in PD and AD. Our research in this area is aimed at trying to figure out the structure and dynamics of the “healthy” stable form of a particular protein associated with PD, α-synuclein. With our collaborators, we have identified a dynamic tetramer of synuclein that appears to resist precipitation and may represent a thermodynamically stable “storage” form of the soluble protein in the cell. We are currently using a combination of NMR and molecular modeling methods that will help us to identify small-molecule drug candidates that stabilize this tetramer in hopes of slowing the onset of PD.

800 MHz ¹H,¹⁵N HSQC of 0.8 mM S oligomer, 25 ^oC, pH 7.0, 0.1% BOG (3 mM).

Proposed α-synuclein tetramer structure based on EM reconstruction and PRE (paramagnetic relaxation enhancement).

Publications

Click on the title to read!

From intrinsically disordered protein to context-dependent folding: The α-synuclein tetramer is teased out of hiding. T. C. Pochapsky, Proc Natl Acad Sci U S A 2015, 112 (31), 9502-9503.
The Dynamic Structure of α-Synuclein Multimers. T. Gurry; O. Ullman; C. K. Fisher; I. Perovic; T. Pochapsky; C. M. Stultz, Journal of the American Chemical Society 2013, 135 (10), 3865-3872.
A soluble α-synuclein construct forms a dynamic tetramer. W. Wang; I. Perovic; J. Chittuluru; A. Kaganovich; L. T. T. Nguyen; J. Liao; J. R. Auclair; D. Johnson; A. Landeru; A. K. Simorellis; S. Ju; M. R. Cookson; F. J. Asturias; J. N. Agar; B. N. Webb; C. Kang; D. Ringe; G. A. Petsko; T. C. Pochapsky; Q. Q. Hoang, Proc Natl Acad Sci U S A 2011, 108 (43), 17797-17802.

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