Mitochondrial dysfunction is a common feature of Parkinson's disease, but our knowledge of the underlying molecular mechanisms is rudimentary. Recently, a genetic pathway that influences mitochondrial integrity has emerged from studies of the PINK1 and parkin genes, loss-of-function mutations of which are responsible for the majority of early-onset recessive forms of parkinsonism. The PINK1 gene encodes a serine/threonine kinase that localizes to the mitochondrial inner membrane space and to the cytoplasm, whereas parkin encodes a ubiquitin-protein ligase that localizes broadly throughout the cell, including the cytoplasm and mitochondria. Mutational analyses of highly-conserved Drosophila orthologs of PINK1 and parkin indicate that PINK1 acts upstream of Parkin in a common pathway that promotes mitochondrial integrity in a subset of tissues, including indirect flight muscle and dopaminergic neurons in the central nervous system. Our recent work indicates that the PINK1/Parkin pathway influences mitochondrial and tissue integrity by promoting mitochondrial fission. We hypothesize from this and other findings that the PINK1/Parkin pathway promotes mitochondrial fission by phosphorylating and/or ubiquitinating particular components of the mitochondrial morphogenesis machinery. We further hypothesize that the cell death accompanying reduced mitochondrial fission in parkin and PINK1 mutants derives from inefficient delivery of damaged mitochondria to autophagosomes, defective trafficking of enlarged (fused) mitochondria to presynaptic nerve terminals, and/or excessive reactive oxygen species production by enlarged mitochondria.
Two specific aims are proposed to address these hypotheses:
the first aim will test whether the PINK1/Parkin pathway activates mitochondrial fission or inhibits mitochondrial fusion by using established mitochondrial fusion and fission assay systems, and by testing candidate substrates of the PINK1/Parkin pathway.
The second aim i nvolves genetic, molecular and cell biological experiments to distinguish between specific models by which impaired mitochondrial fission in PINK1 and parkin mutants influences tissue integrity. From these experiments, we hope to advance our long-term goal of elucidating the mechanisms underlying mitochondrial dysfunction and selective cell death in Parkinson's disease.

Public Health Relevance

Loss-of-function mutations in the parkin or PTEN-induced kinase 1 (PINK1) genes are collectively the most frequent cause of autosomal recessive familial Parkinson's disease. Our proposal aims to understand the biological roles of Parkin and PINK1 and how their mutational inactivation results in neuronal loss. Insight from our studies of PINK1 and Parkin are likely to be relevant to more common idiopathic forms of Parkinson's disease and this insight could lead to the development of preventative treatments for this debilitating disorder.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM086394-01
Application #
7561462
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Anderson, Vernon
Project Start
2009-01-01
Project End
2012-12-31
Budget Start
2009-01-01
Budget End
2009-12-31
Support Year
1
Fiscal Year
2009
Total Cost
$307,750
Indirect Cost
Name
University of Washington
Department
Genetics
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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Thomas, Ruth E; Andrews, Laurie A; Burman, Jonathon L et al. (2014) PINK1-Parkin pathway activity is regulated by degradation of PINK1 in the mitochondrial matrix. PLoS Genet 10:e1004279
Vincow, Evelyn S; Merrihew, Gennifer; Thomas, Ruth E et al. (2013) The PINK1-Parkin pathway promotes both mitophagy and selective respiratory chain turnover in vivo. Proc Natl Acad Sci U S A 110:6400-5
Kim, Nam Chul; Tresse, Emilie; Kolaitis, Regina-Maria et al. (2013) VCP is essential for mitochondrial quality control by PINK1/Parkin and this function is impaired by VCP mutations. Neuron 78:65-80
Hsieh, Edward J; Shulman, Nicholas J; Dai, Dao-Fu et al. (2012) Topograph, a software platform for precursor enrichment corrected global protein turnover measurements. Mol Cell Proteomics 11:1468-74
Burman, Jonathon L; Yu, Selina; Poole, Angela C et al. (2012) Analysis of neural subtypes reveals selective mitochondrial dysfunction in dopaminergic neurons from parkin mutants. Proc Natl Acad Sci U S A 109:10438-43
Poole, Angela C; Thomas, Ruth E; Yu, Selina et al. (2010) The mitochondrial fusion-promoting factor mitofusin is a substrate of the PINK1/parkin pathway. PLoS One 5:e10054