Journal
CELL REPORTS
Volume 18, Issue 4, Pages 918-932Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2016.12.090
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Funding
- NIH/NINDS [NS38377, R01 NS085070]
- JPB Foundation
- Korea Ministry of Science [NRF 2016R1A2B4008271, 2015R1C1A1A01052708]
- Samsung Biomedical Research Institute [SMX1161351, SMX1161191]
- Michael J. Fox Foundation for Parkinson's Research
- Foundation for Mitochondrial Medicine
- Mayo Clinic Foundation
- Centers for Individualized and Regenerative Medicine
- Marriott Family Foundation
- Gerstner Family Career Development Award
- American Parkinson Disease Foundation (APDA)
- NRF [2015R1C1A1A01052708, 2016R1A2B4008271]
- Korea Ministry of Science, ICT & Future Planning
- Samsung Biomedical Research Institute grant [SMX1161351, SMX1161191]
- National Research Foundation of Korea [2015R1C1A1A01052708, 2016R1A2B4008271] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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Mutations in PTEN-induced putative kinase 1 (PINK1) and parkin cause autosomal-recessive Parkinson's disease through a common pathway involving mitochondrial quality control. Parkin inactivation leads to accumulation of the parkin interacting substrate (PARIS, ZNF746) that plays an important role in dopamine cell loss through repression of proliferator-activated receptor gamma coactivator-1-alpha (PGC-1 alpha) promoter activity. Here, we show that PARIS links PINK1 and parkin in a common pathway that regulates dopaminergic neuron survival. PINK1 interacts with and phosphorylates serines 322 and 613 of PARIS to control its ubiquitination and clearance by parkin. PINK1 phosphorylation of PARIS alleviates PARIS toxicity, as well as repression of PGC-1 alpha promoter activity. Conditional knockdown of PINK1 in adult mouse brains leads to a progressive loss of dopaminergic neurons in the substantia nigra that is dependent on PARIS. Altogether, these results uncover a function of PINK1 to direct parkin-PARIS-regulated PGC-1 alpha expression and dopaminergic neuronal survival.
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