Parkinson's disease (PD) is the second most common neurodegenerative disorder in the United States. Recently, several families with Autosomal Recessive Juvenile Parkinsonism (AR-JP) have been demonstrated to carry mutations in a gene termed Parkin, a ubiquitin E3 ligase. NINDS recently identified Parkin and related proteins as targets for intensive investigation (RFA NS-01-005). In this proposal, we focus on Ariadne, the closest known structural homolog of Parkin. Ariadne is a poorly characterized protein with a similar overall structural organization to Parkin. Both Ariadne and Parkin bind to the same ubiquitin E2 enzymes and in Drosophila, loss of Ariadne results in reduced viability and resting tremors. In preliminary studies, we have demonstrated that Ariadne and Parkin share significant structural and functional properties.In this proposal, we will use biochemical, molecular, cellular and genetic methods to test thehypotheses that Ariadne and Parkin are: 1) structural and functional homologs; 2) participate in Lewy Body formation; and 3) protect cells both in vitro and in vivo from noxious stimuli.This work may allow us to: 1) explain why the phenotypic effects of global loss-of-function mutations in Parkin are largely restricted to dopaminergic neurons; 2) verify that Lewy Body-like cytoplasmic inclusions reflect an adaptive response by cells; and 3 provide insight into the functioning of this class of proteins which can enhance our understanding of Parkin function in cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS042898-04
Application #
7002174
Study Section
Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
Program Officer
Murphy, Diane
Project Start
2003-01-15
Project End
2007-11-30
Budget Start
2006-01-01
Budget End
2006-12-31
Support Year
4
Fiscal Year
2006
Total Cost
$284,875
Indirect Cost
Name
University of Massachusetts Amherst
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
153926712
City
Amherst
State
MA
Country
United States
Zip Code
01003
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