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, we have 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. We have 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 we hypothesize 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, we will take advantage of our 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. We propose to screen for new genetic factors as well as for chemical compounds that can 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 #
5P01ES016738-05
Application #
8377576
Study Section
Special Emphasis Panel (ZES1-LWJ-G)
Project Start
Project End
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$155,654
Indirect Cost
$69,948
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Singec, Ilyas; Crain, Andrew M; Hou, Junjie et al. (2016) Quantitative Analysis of Human Pluripotency and Neural Specification by In-Depth (Phospho)Proteomic Profiling. Stem Cell Reports 7:527-42
Qu, Zhe; Greenlief, C Michael; Gu, Zezong (2016) Quantitative Proteomic Approaches for Analysis of Protein S-Nitrosylation. J Proteome Res 15:1-14
Satoh, Takumi; Stalder, Romain; McKercher, Scott R et al. (2015) Nrf2 and HSF-1 Pathway Activation via Hydroquinone-Based Proelectrophilic Small Molecules is Regulated by Electrochemical Oxidation Potential. ASN Neuro 7:
Okamoto, Shu-ichi; Lipton, Stuart A (2015) S-Nitrosylation in neurogenesis and neuronal development. Biochim Biophys Acta 1850:1588-93
Spiering, Sean; Davidovics, Herman; Bushway, Paul J et al. (2015) High content screening for modulators of cardiac differentiation in human pluripotent stem cells. Methods Mol Biol 1263:43-61
Jeon, Gye Sun; Nakamura, Tomohiro; Lee, Jeong-Seon et al. (2014) Potential effect of S-nitrosylated protein disulfide isomerase on mutant SOD1 aggregation and neuronal cell death in amyotrophic lateral sclerosis. Mol Neurobiol 49:796-807
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
Choi, Min Sik; Nakamura, Tomohiro; Cho, Seung-Je et al. (2014) Transnitrosylation from DJ-1 to PTEN attenuates neuronal cell death in parkinson's disease models. J Neurosci 34:15123-31
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
Zhu, Saiyong; Ambasudhan, Rajesh; Sun, Woong et al. (2014) Small molecules enable OCT4-mediated direct reprogramming into expandable human neural stem cells. Cell Res 24:126-9

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