In recent years, mutations in PTEN-induced kinase 1 (PINK1) have been associated with autosomal recessive Parkinsonism. Early studies have uniformly shown a neuroprotective role for PINK1, indicating that studying this familial form of PD may offer valuable insights into potential therapeutic strategies. Dysregulation of mitochondria and autophagy are both centrally implicated in toxin, genetic and environmental approaches to modeling PD. Our preliminary data implicate PINK1 in the upstream regulation of autophagy and in maintenance of mitochondrial interconnectivity, neurite health and synaptic function. Using differentiated neuronal cell lines and primary neuron cultures from control and PINK1 knockout mice, we will determine mechanisms by which PINK1 protects from toxin and genetic PD models, focusing on: 1) the role of subcellular localization in PINK1-mediated neuroprotection, 2) mechanisms regulating PINK1 localization, and 3) identification and characterization of downstream components of the PINK1 signaling pathway, using both candidate and nonbiased proteomic approaches. Achieving the goals of this project to obtain a better understanding of PINK1 regulation, subcellular compartmentalization and downstream pathways will provide insight into new therapeutic strategies to reduce neuronal dysfunction and cell death in PD.

Public Health Relevance

. Loss of function mutations in PTEN-induced kinase 1 (PINK1) contribute to a recessive form of Parkinson's disease. Completion of this study will enhance understanding of mechanisms by which PINK1 confers protection in models of parkinsonian injury, and the subcellular regulation of its functions. Developing this basic knowledge represents a necessary first step towards identification of new therapeutic targets to prevent or slow neurodegeneration in Parkinson's and related diseases.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
High Priority, Short Term Project Award (R56)
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Cell Death in Neurodegeneration Study Section (CDIN)
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Sutherland, Margaret L
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University of Pittsburgh
Schools of Medicine
United States
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