PINK1 regulation of neuronal and mitochondrial homeostasis PROJECT SUMMARY. Mutations in PTEN-induced kinase 1 (PINK1) cause familial autosomal recessive parkinsonism. As PINK1 plays a neuroprotective role in a wide range of genetic and toxin-induced Parkinson's disease (PD) models, studying its function in neurons may offer particular insights into potential therapeutic strategies. In the prior project period, we found that endogenous PINK1 exists in mitochondrial and cytosolic compartments. Moreover, these pools of PINK1 played divergent roles in regulating mitochondrial fission-fusion, mitophagy, calcium homeostasis and dendritic morphogenesis. Using primary neurons, differentiated neuronal cell lines and Pink1 knockout and control mice, the current proposal focuses on studying mechanisms by which PINK1 regulates neuron differentiation and the maintenance of extended axo-dendritic arbors. Based on preliminary data, we hypothesize that PINK1 interacts with cytosolic targets to regulate neuron differentiation and dendritic spine formation. We will study the role of novel PINK1-interacting proteins in regulating dendritogenesis and mitochondrial transport into neurites. The impact of PD-related mutations will be analyzed, and the neuroprotective potential of upregulating downstream pathways tested using Pink1-/- mice. Obtaining a better understanding of neuron-specialized functions of PINK1 in regulating dendritogenesis and compartmentalized mitochondrial content will yield valuable insights towards future strategies to reduce neuron dysfunction in PD.

Public Health Relevance

. Loss-of-function mutations in PTEN-induced kinase 1 (PINK1) contribute to a recessive form of Parkinson's disease. In this proposal, we will focus on mechanisms by which PINK1 promotes the elaboration and maintenance of an extended network of thin cellular extensions that function like communication cables in the brain. We will examine the role of proteins that we discovered can interact with PINK1, and how parkinsonian mutations in PINK1 affect these interactions. Completion of this study will enhance understanding of mitochondrial and cytosolic mechanisms by which PINK1 regulates these structural elements, which are essential for brain cell health and function. This in turn may help identify new strategies 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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Special Emphasis Panel (NOMDM)
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Sutherland, Margaret L
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University of Pittsburgh
Schools of Medicine
United States
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