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

Yunjong Lee, Daniel A. Stevens, SungUng Kang, Haisong Jiang, Yun Il Lee, Hanseok Seok Ko, Leslie A. Scarffe, George Umanah, Hojin Kang, Sangwoo Ham, Tae-In Kam, Kathleen Allen, Saurav Brahmachari, Jungwoo Wren Kim, Stewart Neifert, Seung Pil Yun, Fabienne C. Fiesel, Wolfdieter Springer, Valina Dawson, Joo Ho ShinTed M Dawson

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)918-932
Number of pages15
JournalCell Reports
Volume18
Issue number4
DOIs
StatePublished - Jan 24 2017

Fingerprint

Ubiquitination
Dopaminergic Neurons
Neurons
Phosphorylation
Substantia Nigra
Quality Control
Serine
Quality control
Parkinson Disease
Toxicity
PTEN-induced putative kinase
Dopamine
Brain
Mutation
Substrates

Keywords

  • PARIS
  • parkin
  • Parkinson's disease
  • PGC-1α
  • PINK1
  • ubiquitin
  • ZNF746

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

PINK1 Primes Parkin-Mediated Ubiquitination of PARIS in Dopaminergic Neuronal Survival. / Lee, Yunjong; Stevens, Daniel A.; Kang, SungUng; Jiang, Haisong; Lee, Yun Il; Ko, Hanseok Seok; Scarffe, Leslie A.; Umanah, George; Kang, Hojin; Ham, Sangwoo; Kam, Tae-In; Allen, Kathleen; Brahmachari, Saurav; Kim, Jungwoo Wren; Neifert, Stewart; Yun, Seung Pil; Fiesel, Fabienne C.; Springer, Wolfdieter; Dawson, Valina; Shin, Joo Ho; Dawson, Ted M.

In: Cell Reports, Vol. 18, No. 4, 24.01.2017, p. 918-932.

Research output: Contribution to journalArticle

Lee, Y, Stevens, DA, Kang, S, Jiang, H, Lee, YI, Ko, HS, Scarffe, LA, Umanah, G, Kang, H, Ham, S, Kam, T-I, Allen, K, Brahmachari, S, Kim, JW, Neifert, S, Yun, SP, Fiesel, FC, Springer, W, Dawson, V, Shin, JH & Dawson, TM 2017, 'PINK1 Primes Parkin-Mediated Ubiquitination of PARIS in Dopaminergic Neuronal Survival', Cell Reports, vol. 18, no. 4, pp. 918-932. https://doi.org/10.1016/j.celrep.2016.12.090
Lee, Yunjong ; Stevens, Daniel A. ; Kang, SungUng ; Jiang, Haisong ; Lee, Yun Il ; Ko, Hanseok Seok ; Scarffe, Leslie A. ; Umanah, George ; Kang, Hojin ; Ham, Sangwoo ; Kam, Tae-In ; Allen, Kathleen ; Brahmachari, Saurav ; Kim, Jungwoo Wren ; Neifert, Stewart ; Yun, Seung Pil ; Fiesel, Fabienne C. ; Springer, Wolfdieter ; Dawson, Valina ; Shin, Joo Ho ; Dawson, Ted M. / PINK1 Primes Parkin-Mediated Ubiquitination of PARIS in Dopaminergic Neuronal Survival. In: Cell Reports. 2017 ; Vol. 18, No. 4. pp. 918-932.
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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.",
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AU - Fiesel, Fabienne C.

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