Mitochondria dysfunction and oxidative stress have been suggested to be associated with many neurodegenerative diseases, including Parkinson's Disease (PD). The most direct CAUSALITY evidence of mitochondria dysfunction to PD pathogenesis arises from the newly identified PINK1, a disease gene of familial, recessive early-onset PD. PINK1 protein is a nuclear genome encoded protein with a mitochondria targeting signal peptide and a conserved kinase domain, however, its normal functions and roles in pathogenesis remain to be elucidated. The mutations in PINK1-PD patients are causing the PINK1 proteins to be truncated or most likely functionally inactive. HYPOTHESIS: Our overall hypothesis is that PINK1-PD pathology is caused by disruption of mitochondria functions because the mutant PINK1 protein fails to phosphorylate its normal substrates. To test this hypothesis, we have generated genetic PINK1-/- knockout mice and other valuable reagents, and we propose the following specific aims.
SPECIFIC AIM 1 : we will analyze whether PINK1-/- mice develop progressive motor deficits and neuronal pathology in substantia nigra and other brain regions.
SPECIFIC AIM 2 : Subsequently, but not dependent on the Aim 1 outcome, we will investigate mitochondria dysfunction in PINK1 -/- mice and in PINK1-/- dopaminergic cell lines.
SPECIFIC AIM 3 : Subsequently, but not dependent on the Aim1 outcome, we will identify and confirm the substrates of PINK1 kinase. SIGNIFICANCE: Collectively, the generation and characterization of the PINK1 knockout mice as well as the dopaminergic PINK1-/- cell lines, the investigation of the mitochondria dysfunction caused by PINK1 mutations, and the identification of PINK1 kinase substrates are critical for understanding of the molecular mechanisms of PINK1-PD, for identifying potential therapeutic targets, and for drug screening and testing.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Special Emphasis Panel (ZRG1-NOMD-A (01))
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Sieber, Beth-Anne
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Weill Medical College of Cornell University
Schools of Medicine
New York
United States
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Huang, Yong; Shenoy, Sushila; Lu, Bingwei et al. (2012) Kinase signaling dysfunction in Parkinson's disease: a reverse genetic approach in Drosophila. J Neurogenet 26:158-67
Liu, Wencheng; Acin-Perez, Rebeca; Geghman, Kindiya D et al. (2011) Pink1 regulates the oxidative phosphorylation machinery via mitochondrial fission. Proc Natl Acad Sci U S A 108:12920-4
Vives-Bauza, Cristofol; Zhou, Chun; Huang, Yong et al. (2010) PINK1-dependent recruitment of Parkin to mitochondria in mitophagy. Proc Natl Acad Sci U S A 107:378-83
Liu, Wencheng; Vives-Bauza, Cristofol; Acin-Perez-, Rebeca et al. (2009) PINK1 defect causes mitochondrial dysfunction, proteasomal deficit and alpha-synuclein aggregation in cell culture models of Parkinson's disease. PLoS One 4:e4597