Parkinson's disease, a common neurodegenerative disease, is estimated to affect 340,000 individuals in the United States (1). Although therapies are available to relieve the symptoms of Parkinson's disease, there is an urgent need for treatments that target the underlying causes of the disease (2). Loss of function mutations in PINK1 and Parkin cause familial parkinsonism (3, 4). Recent studies link normal PINK1 and Parkin function to a common pathway that protects against mitochondrial dysfunction. In Drosophila, knockout of PINK1, a mitochondrial kinase, or Parkin, an E3 ubiquitin ligase, leads to progressive loss of mitochondrial integrity followed by death of dopaminergic neurons and muscle degeneration (5-9). Loss of PINK1 or Parkin in human cells and mice also leads to mitochondrial dysfunction, suggesting that PINK1 and Parkin may function in an evolutionarily conserved pathway that maintains mitochondrial integrity (10-14). It was recently shown that Parkin is selectively recruited to dysfunctional mitochondria with low membrane potential to induce their degradation by a process known as autophagy (literally, """"""""self-eating"""""""") (15). Interestingly, kinase-active PINK1, which is required for Parkin recruitment, appears to signal mitochondrial dysfunction to Parkin (15-19). Together these findings suggest a model in which PINK1 and Parkin protect against mitochondrial dysfunction by identifying damaged mitochondria and clearing them from the mitochondrial network. Failure of the PINK1/Parkin quality control pathway may lead to the accumulation of dysfunctional mitochondrial and parkinsonism in some families. How PINK1 targets Parkin to impaired mitochondria and how Parkin induces selective mitochondrial degradation, however, are unknown. The proposed research hypothesizes that Parkin is inducibly phosphorylated by PINK1 at discrete sites to promote its recruitment to mitochondria. Additionally, it hypothesizes that the recruitment of Parkin to mitochondria and its promotion of mitochondrial degradation require binding to specific mitochondrial proteins. To address these hypotheses, the proposed research will use radiolabeling in cell culture and high sensitivity mass spectrometry to identify and quantify changes in Parkin phosphorylation following depolarization. Additionally, quantitative mass spectrometry will be used to identify Parkin binding partners and substrates. Finally, the functional relevance of post-translational modifications to Parkin and binding partners of Parkin will be assessed in cell biology experiments. By clarifying key steps in the PINK1/Parkin quality control pathway, the proposed research hopes to uncover targets for the treatment of Parkinson's disease and other diseases of aging. )

Public Health Relevance

Parkinson's disease, a common neurodegenerative disorder, affects roughly 2% of the population over the age of 65 in the United States, and the burden of the disease is likely to increase as the population ages (1). Although drugs and procedures are available to treat symptoms of the movement disorder, there is an urgent need for therapies that target the underlying causes of the disease (2). By addressing key steps in the PINK1/Parkin quality control pathway, which may protect against the development of parkinsonism (20), the proposed research aims to increase our understanding of disease's pathogenesis and identify novel targets for drug development. )

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30AG039185-02
Application #
8197970
Study Section
Special Emphasis Panel (ZRG1-F05-C (20))
Program Officer
Refolo, Lorenzo
Project Start
2010-09-30
Project End
2012-05-30
Budget Start
2011-09-30
Budget End
2012-05-30
Support Year
2
Fiscal Year
2011
Total Cost
$37,213
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Narendra, Derek P; Wang, Chunxin; Youle, Richard J et al. (2013) PINK1 rendered temperature sensitive by disease-associated and engineered mutations. Hum Mol Genet 22:2572-89
Narendra, Derek; Walker, John E; Youle, Richard (2012) Mitochondrial quality control mediated by PINK1 and Parkin: links to parkinsonism. Cold Spring Harb Perspect Biol 4: