Recently,alpha-synuclein has been identified as a major component of Lewy bodies, the intracellular inclusions that are a pathological hallmark of Parkinson's disease (PD). Our goals in this proposal are to test the hypothesis that a critical step in Parkinson's disease is the aggregation of alpha-synuclein, which leads to the formation of Lewy Bodies and subsequently to neuronal death. Specifically we will determine the molecular basis for alpha-synuclein aggregation and investigate potential inhibitors of alpha-syouclein aggregation. Our preliminary results have revealed a number of factors that lead to a confonnational change in alpha synuclein at neutral pH, and also to aggregation and fibril formation. We plan a systematic characterization of the biophysical properties of alpha-synuclein to determine if there is a correlation between its conformation and its propensity to aggregate, with both wild type and mutant alpha-synucleins. We will investigate whether various factors associated with PD, for example, metal ions and pesticides, enhance the aggregation of alpha-synuclein. Details of the aggregation process will be studied to elucidate the molecular mechanism of aggregation and fibril formation. We will screen a series of peptides and small molecules for inhibitory effects on alpha-synuclein aggregation. These experiments represent critical steps towards elucidating the role of alpha-synuclein in Parkinson's disease. We expect to learn the potential role of various factors, ranging from environmental contaminants to the concentration of alpha-synuclein, in triggering fibril formation. Further, we anticipate fnding inhibitors which may lay the groundwork for potential therapeutic approaches. Techniques to be used include various biophysical/biochemical methods, such as attenuated total reflectance FTIR to analyze the conformaffonal state of aggregated alpha-synuclein, atomic force and electron microscopy to image the aggregates, and kinetic methods to monitor the rate of formation of fibrils.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-MDCN-2 (01))
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Murphy, Diane
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University of California Santa Cruz
Schools of Arts and Sciences
Santa Cruz
United States
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Hong, Dong-Pyo; Han, Shubo; Fink, Anthony L et al. (2011) Characterization of the non-fibrillar ýý-synuclein oligomers. Protein Pept Lett 18:230-40
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Hu, Dongmei; Qin, Zhijie; Xue, Bin et al. (2008) Effect of methionine oxidation on the structural properties, conformational stability, and aggregation of immunoglobulin light chain LEN. Biochemistry 47:8665-77

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