Mutations in the PINK1 gene are linked to an autosomal recessive early onset familial form of Parkinson's disease (PD). The molecular and physiological functions of PINK1 that generate pathological abnormality of PD-associated PINK1 mutants are largely unknown. Therefore, this group has developed a genetic model of PD in Drosophila to study the in vivo role and genetic interactions of PINK1 with known and new potential contributors to this disease. It has been recently shown that inactivation of Drosophila PINK1 (dPINKI) using RNAi results in progressive loss of dopaminergic (DA) neurons and in ommatidial degeneration of the compound eye, which is rescued by expression of human PINK1 (hPINKI). Moreover, expression of human superoxide dismutase 1 (SOD1) suppresses neurodegeneration induced by dPINKI inactivation, and treatment of dPINKI RNAi flies with antioxidants (e.g., vitamin E) significantly inhibits ommatidial degeneration. Thus, PINK1 may normally prevent neurons from undergoing oxidative stress, a potential mechanism by which a reduction in PINK1 function leads to PD-associated neurodegeneration. Therefore, in this proposal it is hypothesized that PINK1 plays a critical role in maintaining survival of dopaminergic neurons via a regulated pathway involving protection against oxidative stress. PD-pathogenic PINK1 mutants impair the functional pathway and therefore lose the ability to protect neurons from oxidative stress. In this study, efforts will focused on utilizing the newly-developed PD fly model (published in PNAS) to first investigate the genetic mechanisms and interactions that influence the severity of the PD pathogenic phenotype produced by PINK1 mutations under different (oxidative) stress conditions. The fact that wild-type human PINK1 but not disease-associated PINK1 mutations can reverse PD-associated pathologies in our fly model provides us with the opportunity to efficiently screen in a whole animal system for genetic and chemical modifiers that are likely relevant to finding therapeutics for this disease. New genetic factors as well as chemical compounds will be screened that function to alter (e.g., ameliorate or aggravate) the neurodegenerative phenotype observed in our PD fly model.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Program Projects (P01)
Project #
5P01ES016738-02
Application #
7687583
Study Section
Special Emphasis Panel (ZES1-LWJ-G (CN))
Program Officer
Lawler, Cindy P
Project Start
2008-09-15
Project End
2013-06-30
Budget Start
2009-07-01
Budget End
2010-06-30
Support Year
2
Fiscal Year
2009
Total Cost
$1,603,108
Indirect Cost
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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Zhou, Hui; Qu, Zhe; Mossine, Valeri V et al. (2014) Proteomic analysis of the effects of aged garlic extract and its FruArg component on lipopolysaccharide-induced neuroinflammatory response in microglial cells. PLoS One 9:e113531
Okamoto, Shu-Ichi; Nakamura, Tomohiro; Cieplak, Piotr et al. (2014) S-nitrosylation-mediated redox transcriptional switch modulates neurogenesis and neuronal cell death. Cell Rep 8:217-28
Chan, Shing Fai; Sances, Sam; Brill, Laurence M et al. (2014) ATM-dependent phosphorylation of MEF2D promotes neuronal survival after DNA damage. J Neurosci 34:4640-53
Qu, Zhe; Meng, Fanjun; Zhou, Hui et al. (2014) NitroDIGE analysis reveals inhibition of protein S-nitrosylation by epigallocatechin gallates in lipopolysaccharide-stimulated microglial cells. J Neuroinflammation 11:17

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