We have been working on how mitochondrial function influences neuronal survival, particularly in the context of inherited forms of parkinsonism. To this end, we have been examining accelerated aging models including one with a mutation in the mitochondrial polymerase gamma that diminishes proofreading activity of the enzyme, leading to accumulation of mitochondrial DNA mutations. We previously reported that, using a series of high content techniques, PolG mutant animals had loss of mitochondrial complex I assembly. Given that previous data from cell culture experiments suggested that DJ-1 deficiency was associated with an increased sensitivity to complex I inhibitors such as rotenone or MPP+, we therefore expected that crossing PolG and DJ-1 animals would result in loss of dopaminergic phenotypes. However, despite extensive investigation in appropriately powered studies we did not find any evidence of neuronal loss in the double mutants.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAG000940-09
Application #
9351988
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Aging
Department
Type
DUNS #
City
State
Country
Zip Code
Soutar, Marc P M; Kempthorne, Liam; Miyakawa, Shuichi et al. (2018) AKT signalling selectively regulates PINK1 mitophagy in SHSY5Y cells and human iPSC-derived neurons. Sci Rep 8:8855
Parrado-Fernández, Cristina; Schneider, Bernadette; Ankarcrona, Maria et al. (2018) Reduction of PINK1 or DJ-1 impair mitochondrial motility in neurites and alter ER-mitochondria contacts. J Cell Mol Med :
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; Niño, 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
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
McCoy, Melissa K; Cookson, Mark R (2011) DJ-1 regulation of mitochondrial function and autophagy through oxidative stress. Autophagy 7:531-2

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