a-synuclein (aSyn) is an intrinsically disordered protein that appears in aggregated form in the brains of patients with Parkinson's disease. The conversion of monomer to aggregate is complex. Aggregation rates of aSyn are very sensitive to changes in amino acid sequence and environmental conditions. Understanding aSyn aggregation requires characterizing the ensemble of conformations adopted by the monomer and correlating them to aggregation behavior. Though many hypotheses have been proposed to relate aSyn's aggregation behavior to its interconverting conformational ensembles, a consistent molecular description of the aSyn conformational ensembles and their relationship to aggregation remains elusive. This proposal integrates NMR and computational approaches to characterize and explicitly visualize the intrinsically disordered conformational ensembles of aSyn and the early stages of aggregation under different sequence and environmental conditions. The goal is to identify the elements of transient 2o and/or 3o structure that are key for initiation of aggregation and determine their stabilizing driving forces. Identifying the structural basis of aSyn monomer aggregation propensity may be critical for developing inhibitors for the aggregation steps that precede the toxic aggregation cascade. Once developed, this integrated approach can be applied to other important biological functions or diseases involving intrinsically disordered proteins.

Public Health Relevance

Parkinson's disease is the second most prevalent of the late onset neurodegenerative diseases. a-synuclein, an extremely important protein involved in the etiology of Parkinson's disease will be modeled at the molecular level by integrating NMR and computational approaches. Understanding the role of the monomeric conformational ensembles of a-synuclein may be critical for developing inhibition strategies against amyloid formation.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Macromolecular Structure and Function B Study Section (MSFB)
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Wehrle, Janna P
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Rutgers University
Schools of Arts and Sciences
New Brunswick
United States
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Kim, Seho; Wu, Kuen-Phon; Baum, Jean (2013) Fast hydrogen exchange affects ýýýýýN relaxation measurements in intrinsically disordered proteins. J Biomol NMR 55:249-56
Kang, Lijuan; Janowska, Maria K; Moriarty, Gina M et al. (2013) Mechanistic insight into the relationship between N-terminal acetylation of *-synuclein and fibril formation rates by NMR and fluorescence. PLoS One 8:e75018
Moriarty, Gina M; Janowska, Maria K; Kang, Lijuan et al. (2013) Exploring the accessible conformations of N-terminal acetylated *-synuclein. FEBS Lett 587:1128-38
Narayanan, Chitra; Weinstock, Daniel S; Wu, Kuen-Phon et al. (2012) Investigation of the Polymeric Properties of ?-Synuclein and Comparison with NMR Experiments: A Replica Exchange Molecular Dynamics Study. J Chem Theory Comput 8:3929-3942
Kang, Lijuan; Moriarty, Gina M; Woods, Lucy A et al. (2012) N-terminal acetylation of ?-synuclein induces increased transient helical propensity and decreased aggregation rates in the intrinsically disordered monomer. Protein Sci 21:911-7
Parmar, Avanish S; Nunes, Ana Monica; Baum, Jean et al. (2012) A peptide study of the relationship between the collagen triple-helix and amyloid. Biopolymers 97:795-806
Wu, Kuen-Phon; Baum, Jean (2011) Backbone assignment and dynamics of human ?-synuclein in viscous 2 M glucose solution. Biomol NMR Assign 5:43-6
Kang, Lijuan; Wu, Kuen-Phon; Vendruscolo, Michele et al. (2011) The A53T mutation is key in defining the differences in the aggregation kinetics of human and mouse ?-synuclein. J Am Chem Soc 133:13465-70
Wu, Kuen-Phon; Baum, Jean (2010) Detection of transient interchain interactions in the intrinsically disordered protein alpha-synuclein by NMR paramagnetic relaxation enhancement. J Am Chem Soc 132:5546-7