Alpha-Synuclein (alpha-S) is a 140 amino acid, intrinsically disordered protein that adopts an amphipathic alpha-helical structure upon binding the membrane. Alpha-S is the major proteinaceous component of insoluble fibrillar Lewy bodies, a hallmark of Parkinson's disease (PD). The precise roles of both native and pathological forms of alpha-S remain unclear. However, the interaction of alpha-S with cellular membranes is now thought to be critical to its native function, and potentially to its role in PD as well. We propos a series of Low-Angle X-ray Scattering (LAXS) experiments and molecular dynamics (MD) simulations to more fully understand the membrane remodeling effects of native alpha-S. We will be primarily focused on the role of lipid composition and bilayer curvature. In particular, we propose the following two specific aims, each of which will be carried out in parallel: 1) Determine how alpha-S remodels membranes when bound to both monolayer leaflets. 2) Determine how alpha-S remodels membranes when bound to only one leaflet, modeling its physiological action on synaptic vesicles. Each of these aims will test our hypothesis that the intrinsic, natural curvature of alpha-S dictates its capacity to remodel and stabilize membranes, in particular those that are highly curved (like synaptic vesicles).

Public Health Relevance

The membrane protein alpha-synuclein has been implicated as playing a central role in both sporadic and familial forms of Parkinson's disease, the most common neurodegenerative movement disorder. Through developing a biophysical understanding of alpha-synuclein induced membrane remodeling, we will gain insight into the native function of alpha--synuclein, and in turn be well positioned to begin to understand its role in the disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31NS077634-01A1
Application #
8314956
Study Section
Special Emphasis Panel (ZRG1-F03B-G (20))
Program Officer
Sutherland, Margaret L
Project Start
2012-05-29
Project End
2015-05-28
Budget Start
2012-05-29
Budget End
2013-05-28
Support Year
1
Fiscal Year
2012
Total Cost
$27,435
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Boscia, Alexander L; Treece, Bradley W; Mohammadyani, Dariush et al. (2014) X-ray structure, thermodynamics, elastic properties and MD simulations of cardiolipin/dimyristoylphosphatidylcholine mixed membranes. Chem Phys Lipids 178:1-10
Braun, Anthony R; Lacy, Michael M; Ducas, Vanessa C et al. (2014) ?-Synuclein-induced membrane remodeling is driven by binding affinity, partition depth, and interleaflet order asymmetry. J Am Chem Soc 136:9962-72