Genetic basis for alpha-synuclein toxicity

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DESCRIPTION (provided by applicant): Mutations and environmental factors are known to induce various post-translational alterations in alpha- synuclein, with alterations in alpha-synuclein playing an important role in the onset and progression of Parkinson's disease (PD). In particular, increases in alpha-synuclein insolubility and alpha-synuclein aggregation appear to be central events in the pathogenesis and neurotoxicity observed in PD, as well as experimental models of PD. Aging is a major risk factor for PD and related synucleinopathies, although the underlying genetic basis for age-related alterations to alpha-synuclein is not currently known. Identifying each of the genes which negatively, as well as positively, regulate age-related changes in alpha-synuclein within post-mitotic neurons is likely to lead to a better understanding of the molecular basis for the onset and progression of pathogenesis in PD, as well as potentially lead to the development of novel therapeutics for the treatment of PD. A number of mutations in alpha-synuclein have been identified in recent years, with mutations in alpha-synuclein observed to promote some familial forms of PD. As with aging, it is important to identify the genes which positively and negatively regulate the pathogenesis and, toxicity associated with mutant alpha-synuclein in post-mitotic neurons. The Saccharomyces cerevisiae (S. cerevisiae) model system has been demonstrated to be useful for studying cellular aging, with the stationary phase model of aging contributing to our understanding of post- mitotic cell aging. Additionally, S. cerevisiae have proved useful in studying the biology of many human genes, including mutant human genes associated with disease. The focus of the current proposal is to test the hypothesis that mutagenesis experimentation with the S. cerevisiae stationary phase model of aging aid in developing an understanding of the genetic basis for age-related alterations to wild-type and mutant alpha- synuclein aggregation/insolubility, and age-related increases in wild-type and mutant alpha-synuclein toxicity. Studies will be conducted in cells expressing wild-type and mutant (A53T.A30P) alpha-synuclein. The specific aims are as follows: 1) To utilize mutagenesis to understand the genetic basis for the age-related alterations which occur to alpha-synuclein 2) To utilize mutagenesis to understand the genetic regulation of age-related increases in alpha-synuclein toxicity 3) To confirm the experimental validity, and implications for PD, each of the data obtained in the preceding specific aims.