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

Proc Natl Acad Sci U S A. 2015 Sep 15;112(37):11696-701. doi: 10.1073/pnas.1500624112. Epub 2015 Aug 31.

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.

Keywords: PARIS; Parkinson's disease; ZNF746; mitochondrial biogenesis; parkin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / embryology
  • Brain / metabolism
  • Cell Death
  • Cell Line, Tumor
  • Dopamine / metabolism
  • Dopaminergic Neurons / metabolism
  • Gene Expression Regulation
  • Green Fluorescent Proteins / metabolism
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / metabolism*
  • Neurons / metabolism
  • Oxygen Consumption
  • Parkinson Disease / metabolism
  • Repressor Proteins / physiology
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / physiology*

Substances

  • Repressor Proteins
  • ZNF746 protein, mouse
  • Green Fluorescent Proteins
  • Ubiquitin-Protein Ligases
  • parkin protein
  • Dopamine