The study of mitochondrial respiratory activity, such as complex I activity, in Parkinson's disease (PD) is an exceptionally active research area that has attracted numerous investigators. Our proposal is novel, however, because it is based on 3 new observations: (l) The deficiency in mitochondrial respiration in PD is expressed by human skin fibroblasts, representing a cell type that undergoes active cell division in culture to provide a continuing supply of cells for experimentation; (2) A deficit in mitochondrial respiration can be induced in normal cells by exposure to L-dopa, an agent widely used in the treatment of idiopathic PD; (3) Ascorbate, an antioxidant, enhances mitochondrial respiratory activity in control fibroblasts and blocks the decline in activity induced by exposure to L-dopa. These observations open a new window into (a) the effect of oxidative stress in mitochondrial function and (b) the significance and regulation of complex I activity. The proposed new studies will include: Comparison of mitochondrial respiratory activity in PD with other neurological disorders and appropriate controls (Aim l); further characterization of the defect in PD (Aim 2); assessment of cellular and mitochondrial antioxidant defenses in control and PD fibroblasts (Aim 3); evaluation of susceptibility of mitochondrial respiration to oxidative stress in PD and control fibroblasts, as well as in mesencephalic cell cultures containing dopaminergic neurons (Aim 4); and evaluation of antioxidant treatment for improvement of mitochondrial respiration in fibroblasts and neuronal cell cultures (Aim 5). Our studies will provide basic information on the possible causes of deficits in mitochondrial respiration in PD and on the effects of antioxidants on mitochondrial function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS034354-03
Application #
2519977
Study Section
Neurology B Subcommittee 2 (NEUB)
Program Officer
Oliver, Eugene J
Project Start
1995-09-01
Project End
1999-08-31
Budget Start
1997-09-01
Budget End
1999-08-31
Support Year
3
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Neurology
Type
Schools of Medicine
DUNS #
114400633
City
New York
State
NY
Country
United States
Zip Code
10029
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Mytilineou, C; Leonardi, E K; Radcliffe, P et al. (1998) Deprenyl and desmethylselegiline protect mesencephalic neurons from toxicity induced by glutathione depletion. J Pharmacol Exp Ther 284:700-6