Parkinson?s disease (PD)/Parkinson?s disease dementia (PDD) is the second most common chronic, neurodegenerative disorder. It is characterized by the loss of dopaminergic neurons from the substantia nigra, often with extension of pathology into the cortex. The pathogenic mechanism underlying this degeneration remains poorly understood, though analysis of gene products mutated in familial parkinsonisms has contributed to our understanding of PD/PDD pathogenesis. One of these PD-associated gene products, PTEN induced kinase 1 (PINK1), has been shown to prevent cell death induced by parkinsonian injury. However, the mechanisms underlying this protection remain poorly understood. My preliminary data indicate that PINK1 regulates mitochondrial egress from the soma into the dendrites. I have also found that PINK1 regulates phosphorylation of cytoplasmic dynein. These discoveries have led me to hypothesize that PINK1 promotes mitochondrial transport into dendrites by regulating phosphorylation of dynein. I will use advanced microscopic, biochemical, and molecular techniques to determine whether the novel PINK1 regulated phosphorylation of dynein regulates its effects on mitochondrial transport. I will also study the impact of PD-linked PINK1 mutations on dynein phosphorylation and mitochondrial transport. In addition to providing me with predoctoral training, this research proposal will help elucidate mechanisms by which PINK1 regulates mitochondrial distribution in neurons and provide insight into mechanisms underlying PD/PDD pathogenesis.

Public Health Relevance

Given the aging demographic in the U.S., age-related neurodegenerative disorders, such as Parkinson?s disease, are becoming a major public health concern. Elucidation of neuroprotective mechanisms mediated by PTEN-induced kinase 1, whose loss of function contributes to familial parkinsonism, may enable the development of new therapeutic strategies

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31NS108504-01A1
Application #
9833147
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Sieber, Beth-Anne
Project Start
2019-11-01
Project End
2021-10-31
Budget Start
2019-11-01
Budget End
2020-10-31
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Pathology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213