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PINK1 Primes Parkin-Mediated Ubiquitination of PARIS in Dopaminergic Neuronal Survival

Title
PINK1 Primes Parkin-Mediated Ubiquitination of PARIS in Dopaminergic Neuronal Survival
Authors
Lee, YunjongStevens, Daniel A.Kang, Sung-UngJiang, HaisongLee, Yun-IlKo, Han SeokScarffe, Leslie A.Umanah, George E.Kang, HojinHam, SangwooKam, Tae-InAllen, KathleenBrahmachari, SauravKim, Jungwoo WrenNeifert, StewartYun, Seung PilFiesel, Fabienne C.Springer, WolfdieterDawson, Valina L.Shin, Joo-HoDawson, Ted M.
DGIST Authors
Lee, Yun-Il
Issue Date
2017-01-24
Citation
Cell Reports, 18(4), 918-932
Type
Article
Article Type
Article
Keywords
Activate ParkinAlpha SynucleinAutoinhibited StateDiseaseLigase ActivityMitochondrial Quality ControlMitophagyPINK1 Dependent PhosphorylationSkeletal MuscleSubcellular Distribution
ISSN
2211-1247
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-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.
URI
http://hdl.handle.net/20.500.11750/4247
DOI
10.1016/j.celrep.2016.12.090
Publisher
CELL PRESS
Files:
There are no files associated with this item.
Collection:
Well Aging Research Center1. Journal Articles


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