@article{7d71330ce36342efa8fb7df71b05121a,
title = "PINK1 Primes Parkin-Mediated Ubiquitination of PARIS in Dopaminergic Neuronal Survival",
abstract = "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-1α) 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-1α 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-1α expression and dopaminergic neuronal survival.",
keywords = "PARIS, PGC-1α, PINK1, Parkinson's disease, ZNF746, parkin, ubiquitin",
author = "Yunjong Lee and Stevens, {Daniel A.} and Kang, {Sung Ung} and Haisong Jiang and Lee, {Yun Il} and Ko, {Han Seok} and Scarffe, {Leslie A.} and Umanah, {George E.} and Hojin Kang and Sangwoo Ham and Kam, {Tae In} and Kathleen Allen and Saurav Brahmachari and Kim, {Jungwoo Wren} and Stewart Neifert and Yun, {Seung Pil} and Fiesel, {Fabienne C.} and Wolfdieter Springer and Dawson, {Valina L.} and Shin, {Joo Ho} and Dawson, {Ted M.}",
note = "Funding Information: This work was supported by grants from the NIH/NINDS NS38377, the JPB Foundation, Korea Ministry of Science (NRF 2016R1A2B4008271 and 2015R1C1A1A01052708), and Samsung Biomedical Research Institute (SMX1161351 and SMX1161191). The authors acknowledge the joint participation by the Adrienne Helis Malvin Medical Research Foundation and the Diana Helis Henry Medical Research Foundation through their direct engagement in the continuous active conduct of medical research, in conjunction with the Johns Hopkins Hospital, the Johns Hopkins University School of Medicine, and the foundation's Parkinson's Disease programs M-1, M-2, and H-2014. T.M.D. is the Leonard and Madlyn Abramson Professor in Neurodegenerative Diseases. W.S. was supported by NIH/NINDS R01 NS085070, the Michael J. Fox Foundation for Parkinson's Research, the Foundation for Mitochondrial Medicine, the Mayo Clinic Foundation, the Centers for Individualized and Regenerative Medicine, the Marriott Family Foundation, and a Gerstner Family Career Development Award. F.C.F. is the recipient of a fellowship from the American Parkinson Disease Foundation (APDA). This research was also supported by grants from the NRF (2016R1A2B4008271 and 2015R1C1A1A01052708) funded by the Korea Ministry of Science, ICT & Future Planning, and by a Samsung Biomedical Research Institute grant (SMX1161351 and SMX1161191). T.M.D. and V.L.D. are founders of Valted, LLC, and hold an ownership equity interest in the company. This arrangement has been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies. Publisher Copyright: {\textcopyright} 2017 The Author(s)",
year = "2017",
month = jan,
day = "24",
doi = "10.1016/j.celrep.2016.12.090",
language = "English (US)",
volume = "18",
pages = "918--932",
journal = "Cell reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "4",
}