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

Yunjong Lee, Daniel A. Stevens, Sung Ung Kang, Haisong Jiang, Yun Il Lee, Han Seok Ko, Leslie A. Scarffe, George E. 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 L. Dawson, Joo Ho ShinTed M. Dawson

Research output: Contribution to journalArticle

61 Scopus citations

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

Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Lee, Y., Stevens, D. A., Kang, S. U., Jiang, H., Lee, Y. I., Ko, H. S., Scarffe, L. A., Umanah, G. E., Kang, H., Ham, S., Kam, T. I., Allen, K., Brahmachari, S., Kim, J. W., Neifert, S., Yun, S. P., Fiesel, F. C., Springer, W., Dawson, V. L., ... Dawson, T. M. (2017). PINK1 Primes Parkin-Mediated Ubiquitination of PARIS in Dopaminergic Neuronal Survival. Cell reports, 18(4), 918-932. https://doi.org/10.1016/j.celrep.2016.12.090