We have recently found in our preliminary studies that parkin, PINK1 and DJ-1 form a complex to promote ubiquitination and degradation of the parkin substrates, parkin and synphilin-1. Pathogenic parkin and PINK1 mutants show impaired ability to degrade parkin and synphilin-1. Our identification of, to our knowledge, the first human early onset recessive PD case with digenic inheritance of PINK1 and DJ-1 mutations, provides in vivo evidence of functional interaction of PINK1 and DJ-1. Moreover, overexpression of parkin in cells genetically ablated for either PINK1 or DJ-1 results in parkin accumulation, suggesting an essential role of the parkin/PINK1/DJ-1 complex in acute protein degradation. Furthermore, S-nitrosylation (transfer of the NO group to a critical cysteine thiol) of PD-related proteins can affect their function and subsequent protein misfolding and aggregation, as in the case of parkin, DJ-1 and protein-disulfide isomerase (PDI) (as studied in Project 3). Together, these findings indicate that impairments to ubiquitinproteasomal pathways by mutations of parkin, PINK1 or DJ-1 contribute to a common pathogenic mechanism of PD, which warrants a further investigation. We hypothesize that parkin, PINK1 and DJ-1 form a functional E3 ligase complex to degrade unfolded/misfolded proteins induced by either oxidative stress or abnormal posttranslational modification. Disease-associated mutations should impair E3 ligase activity of the complex, resulting in increased susceptibility of stress-induced protein aggregation and neurodegeneration. In this proposed study, we will investigate regulation of formation and activity of the parkin/PINK1/DJ-1 complex by each complex component, and by nitrosative or oxidative stress. Moreover, we will determine the contribution of the parkin/PINK1/DJ-1 complex impairment to Lewy body-like aggregate formation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Program Projects (P01)
Project #
5P01ES016738-02
Application #
7880656
Study Section
Special Emphasis Panel (ZES1)
Project Start
Project End
Budget Start
2009-07-01
Budget End
2010-06-30
Support Year
2
Fiscal Year
2009
Total Cost
$143,093
Indirect Cost
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Oh, Chang-Ki; Sultan, Abdullah; Platzer, Joseph et al. (2017) S-Nitrosylation of PINK1 Attenuates PINK1/Parkin-Dependent Mitophagy in hiPSC-Based Parkinson's Disease Models. Cell Rep 21:2171-2182
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 7:527-542
Qu, Zhe; Greenlief, C Michael; Gu, Zezong (2016) Quantitative Proteomic Approaches for Analysis of Protein S-Nitrosylation. J Proteome Res 15:1-14
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
Okamoto, Shu-ichi; Lipton, Stuart A (2015) S-Nitrosylation in neurogenesis and neuronal development. Biochim Biophys Acta 1850:1588-93
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:
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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