Grants and Contracts Details
Description
Mutations and environmental factors are known to induce various post-translational alterations in alphasynuclein,
with alterations in alpha-synuclein playing an important role in the onset and progression of
Parkinson's disease (PO). In particular, increases in alpha-synuclein insolubility and alpha-synuclein
aggregation appear to be central events in the pathogenesis and neurotoxicity observed in PO, as well as
experimental models of PD. Aging is a major risk factor for PO 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 PO, as well as potentially lead to the development of novel therapeutics for
the treatment of PO. 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-synculein in post-mitotic neurons.
The Saccharomyces cerevisiae (5. 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 postimitotic
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
lin developing an understanding of the genetic basis for age-related alterations to wild-type and mutant alphasynuclein
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
PO, each of the data obtained in the preceding specific aims.
Status | Finished |
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Effective start/end date | 5/15/06 → 12/24/07 |
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