Parkinson's disease is the second most common neurodegenerative disease associated with aging. Mutations in PTEN induced kinase 1 (PINK1) and PARKIN cause autosomal recessive forms and some sporadic cases of Parkinson's disease. PINK1 encodes a putative serine/threonine kinase with a mitochondrial targeting sequence, whereas PARKIN encodes a putative E3 ubiquitin ligase. Drosophila melanogaster contains single homologs of pink1 and parkin, and the residues mutated in versions of PINK1 associated with human disease are largely conserved in flies. We have previously shown that loss of pink1 in Drosophila results in male sterility, muscle degeneration and stress sensitivity due to defects in mitochondrial morphology and function. Moreover, pink1 and parkin function in the same genetic pathway, with pink1 positively regulating parkin. In addition, expression of human PINK1 in pink1 mutant flies rescues the pink1 mutant phenotypes, suggesting that human and Drosophila pink1 are functionally conserved. We will study how Pink1 and Parkin interact to regulate mitochondrial function. In addition, we will carry out genetic screens to identify other components of the pink1/parkin pathway. Many neurodegenerative disorders of aging are associated with mitochondrial dysfunction. The identification of new components in the pink1/parkin pathway is likely to provide insight in pathogenesis of these diseases, as well as Parkinson's disease, and may identify new diagnostic tools and therapeutic targets. Our long-term goal, which may require collaborations with other labs, is to explore functions of pink1/parkin pathway components in mammals and to search for potential mutations in these genes in Parkinson's disease patients, and mechanisms by which defects in this pathway can be suppressed. UCLA provides an excellent environment for research on molecular mechanisms of aging- related neurodegenerative diseases. This KO2 award, if funded, will protect the candidate's research time from overextended clinical duties to allow further research development.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Scientist Development Award - Research (K02)
Project #
5K02AG031915-04
Application #
8059592
Study Section
National Institute on Aging Initial Review Group (NIA)
Program Officer
Chen, Wen G
Project Start
2008-05-15
Project End
2013-04-30
Budget Start
2011-05-01
Budget End
2012-04-30
Support Year
4
Fiscal Year
2011
Total Cost
$142,798
Indirect Cost
Name
University of California Los Angeles
Department
Neurology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Hay, Bruce A; Chen, Chun-Hong; Ward, Catherine M et al. (2010) Engineering the genomes of wild insect populations: challenges, and opportunities provided by synthetic Medea selfish genetic elements. J Insect Physiol 56:1402-13
Yun, Jina; Cao, Joseph H; Dodson, Mark W et al. (2008) Loss-of-function analysis suggests that Omi/HtrA2 is not an essential component of the PINK1/PARKIN pathway in vivo. J Neurosci 28:14500-10