Parkin loss leads to Paris-dependent declines in mitochondrial mass and respiration

Daniel A. Stevens, Yunjong Lee, Ho Chul Kang, Byoung Dae Lee, Yun Il Lee, Aaron Bower, Haisong Jiang, Sung Ung Kang, Shaida A. Andrabi, Valina L. Dawson, Joo Ho Shin, Ted M. Dawson

Research output: Contribution to journalArticle

Abstract

Mutations in parkin lead to early-onset autosomal recessive Parkinson's disease (PD) and inactivation of parkin is thought to contribute to sporadic PD. Adult knockout of parkin in the ventral midbrain of mice leads to an age-dependent loss of dopamine neurons that is dependent on the accumulation of parkin interacting substrate (PARIS), zinc finger protein 746 (ZNF746), and its transcriptional repression of PGC-1α. Here we show that adult knockout of parkin in mouse ventral midbrain leads to decreases in mitochondrial size, number, and protein markers consistent with a defect in mitochondrial biogenesis. This decrease in mitochondrial mass is prevented by short hairpin RNA knockdown of PARIS. PARIS overexpression in mouse ventral midbrain leads to decreases in mitochondrial number and protein markers and PGC- 1α-dependent deficits in mitochondrial respiration. Taken together, these results suggest that parkin loss impairs mitochondrial biogenesis, leading to declining function of the mitochondrial pool and cell death.

Original languageEnglish (US)
Pages (from-to)11696-11701
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number37
DOIs
StatePublished - Sep 15 2015

Keywords

  • Mitochondrial biogenesis
  • PARIS
  • Parkin
  • Parkinson's disease
  • ZNF746

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Parkin loss leads to Paris-dependent declines in mitochondrial mass and respiration'. Together they form a unique fingerprint.

  • Cite this