Genetic deficiency of the mitochondrial protein PGAM5 causes a Parkinson's-like movement disorder

Nat Commun. 2014 Sep 15;5:4930. doi: 10.1038/ncomms5930.

Abstract

Mitophagy is a specialized form of autophagy that selectively disposes of dysfunctional mitochondria. Delineating the molecular regulation of mitophagy is of great importance because defects in this process lead to a variety of mitochondrial diseases. Here we report that mice deficient for the mitochondrial protein, phosphoglycerate mutase family member 5 (PGAM5), displayed a Parkinson's-like movement phenotype. We determined biochemically that PGAM5 is required for the stabilization of the mitophagy-inducing protein PINK1 on damaged mitochondria. Loss of PGAM5 disables PINK1-mediated mitophagy in vitro and leads to dopaminergic neurodegeneration and mild dopamine loss in vivo. Our data indicate that PGAM5 is a regulator of mitophagy essential for mitochondrial turnover and serves a cytoprotective function in dopaminergic neurons in vivo. Moreover, PGAM5 may provide a molecular link to study mitochondrial homeostasis and the pathogenesis of a movement disorder similar to Parkinson's disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal
  • Disease Models, Animal
  • Dopamine / deficiency
  • Dopaminergic Neurons / metabolism*
  • Dopaminergic Neurons / pathology
  • Female
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Gene Expression Regulation
  • Mice
  • Mice, Knockout
  • Mitochondria / genetics*
  • Mitochondria / metabolism
  • Mitochondria / pathology
  • Mitochondrial Proteins / deficiency
  • Mitochondrial Proteins / genetics*
  • Mitophagy / genetics
  • Motor Activity
  • Parkinson Disease, Secondary / genetics*
  • Parkinson Disease, Secondary / metabolism
  • Parkinson Disease, Secondary / pathology
  • Phosphoprotein Phosphatases
  • Phosphoric Monoester Hydrolases / antagonists & inhibitors
  • Phosphoric Monoester Hydrolases / deficiency
  • Phosphoric Monoester Hydrolases / genetics*
  • Protein Kinases / genetics*
  • Protein Kinases / metabolism
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Signal Transduction

Substances

  • Mitochondrial Proteins
  • RNA, Small Interfering
  • Protein Kinases
  • PTEN-induced putative kinase
  • PGAM5 protein, mouse
  • Phosphoprotein Phosphatases
  • Phosphoric Monoester Hydrolases
  • Dopamine