Loss of function mutations in either of the genes PINK1 or parkin are associated with autosomal recessive parkinsonism in humans. It is known that these two genes are linked in a single genetic pathway that normally prevents age-dependent mitochondrial dysfunction in Drosophila models. PINK1, which is a mitochondrial kinase has also been shown to support the recruitment of parkin to damaged or depolarized mitochondria. Once recruited to damaged organelles, parkin promotes their turnover via mitophagy, a specialized form of autophagy that acts as a form of mitochondrial quality control. Although several publications have outlined some of the essential molecules involved in PINK1-dependent parkin recruitment and subsequent mitophagy, many details are still unclear. For example, what occurs in depolarized mitochondria to trigger PINK1 activation is poorly understood.
The aim of this project is to understand the molecular basis of the relationship between PINK1 and parkin. To this end, we recently have completed a large shRNA screen against depolarization-induced parkin relocalization to find novel participants in this process. We were able to recover PINK1, showing that the screen worked, and are now validating additional genes. To date we have been able to confirm at least one other gene as well as PINK1, which happens to also be a mitochondrial protein. Functional assays in cell lines and in neurons suggest that this protein is upstream of PINK1 genetically although the mechanism by which it promotes PINK1 recruitment is still under investigation.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAG000940-05
Application #
8552518
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2012
Total Cost
$374,772
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
Zip Code
Hauser, David N; Primiani, Christopher T; Cookson, Mark R (2017) The Effects of Variants in the Parkin, PINK1, and DJ-1 Genes along with Evidence for their Pathogenicity. Curr Protein Pept Sci 18:702-714
Hauser, David N; Primiani, Christopher T; Langston, Rebekah G et al. (2015) The Polg Mutator Phenotype Does Not Cause Dopaminergic Neurodegeneration in DJ-1-Deficient Mice. eNeuro 2:
Rojas-Charry, Liliana; Cookson, Mark R; NiƱo, Andrea et al. (2014) Downregulation of Pink1 influences mitochondrial fusion-fission machinery and sensitizes to neurotoxins in dopaminergic cells. Neurotoxicology 44:140-8
Hauser, David N; Dillman, Allissa A; Ding, Jinhui et al. (2014) Post-translational decrease in respiratory chain proteins in the Polg mutator mouse brain. PLoS One 9:e94646
McCoy, Melissa K; Kaganovich, Alice; Rudenko, Iakov N et al. (2013) Hexokinase activity is required for recruitment of parkin to depolarized mitochondria. Hum Mol Genet :
McCoy, Melissa K; Cookson, Mark R (2012) Mitochondrial quality control and dynamics in Parkinson's disease. Antioxid Redox Signal 16:869-82
McCoy, Melissa K; Cookson, Mark R (2011) DJ-1 regulation of mitochondrial function and autophagy through oxidative stress. Autophagy 7:531-2
Thomas, Kelly Jean; McCoy, Melissa K; Blackinton, Jeff et al. (2011) DJ-1 acts in parallel to the PINK1/parkin pathway to control mitochondrial function and autophagy. Hum Mol Genet 20:40-50
Narendra, Derek P; Jin, Seok Min; Tanaka, Atsushi et al. (2010) PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol 8:e1000298
Cookson, Mark R (2010) DJ-1, PINK1, and their effects on mitochondrial pathways. Mov Disord 25 Suppl 1:S44-8

Showing the most recent 10 out of 13 publications