Parkinson's disease (PD) is a slowly progressive but devastating neurodegenerative disorder that afflicts over 1 million Americans. The etiology of Parkinson's disease has posed a particularly challenging problem to investigate, in large part because of the lengthy disease course. Pathological studies have correlated cellular oxidative stress or protein misfolding with PD. The identification of several genes that underlie familial, inherited forms of PD has allowed for a molecular approach to PD. Recently, mutations in DJ-1 have been found to lead to autosomal recessive, early onset PD. The clinical history of DJ-1-associated familial PD is typical of the disease, including rest tremor, rigidity, gait difficulty, and responsiveness to levodopa treatment. Functional neuroimaging of the brain reveals a presynaptic dopamine deficit consistent with PD. The normal cellular function of DJ-1 is unknown, but the ubiquitous expression of DJ-1 in vertebrates and the high degree of conservation among DJ-1 homologues among diverse species suggest that DJ-1 subserves important cellular functions. DJ-1 homologues have been implicated in several biochemical and cellular roles including protease, amidotransferase, catalase, and chaperone activities, complicating the interpretation of DJ-1 function. The expression of DJ-1 and homologues is induced ii cellular stress responses, suggesting a possible link between DJ-1 mutation and PD pathology. Our preliminary data indicate that DJ-1 is a redox-dependent molecular chaperone that plays an important role in the cellular response to oxidative stress. We propose to investigate the mechanism of DJ-1 activity using complementary biochemical, cellular, and mouse genetic approaches. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS049070-03
Application #
7267048
Study Section
Neurodegeneration and Biology of Glia Study Section (NDBG)
Program Officer
Sieber, Beth-Anne
Project Start
2005-07-01
Project End
2010-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
3
Fiscal Year
2007
Total Cost
$348,373
Indirect Cost
Name
Columbia University (N.Y.)
Department
Pathology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032