Loss of the Parkinson's disease-linked gene DJ-1 perturbs mitochondrial dynamics

Abstract

Growing evidence highlights a role for mitochondrial dysfunction and oxidative stress as underlying contributors to Parkinson's disease (PD) pathogenesis. DJ-1 (PARK7) is a recently identified recessive familial PD gene. Its loss leads to increased susceptibility of neurons to oxidative stress and death. However, its mechanism of action is not fully understood. Presently, we report that DJ-1 deficiency in cell lines, cultured neurons, mouse brain and lymphoblast cells derived from DJ-1 patients display aberrant mitochondrial morphology. We also show that these DJ-1-dependent mitochondrial defects contribute to oxidative stress-induced sensitivity to cell death since reversal of this fragmented mitochondrial phenotype abrogates neuronal cell death. Reactive oxygen species (ROS) appear to play a critical role in the observed defects, as ROS scavengers rescue the phenotype and mitochondria isolated from DJ-1 deficient animals produce more ROS compared with control. Importantly, the aberrant mitochondrial phenotype can be rescued by the expression of Pink1 and Parkin, two PD-linked genes involved in regulating mitochondrial dynamics and quality control. Finally, we show that DJ-1 deficiency leads to altered autophagy in murine and human cells. Our findings define a mechanism by which the DJ-1-dependent mitochondrial defects contribute to the increased sensitivity to oxidative stress-induced cell death that has been previously reported.

PINK1 as a Molecular Checkpoint in the Maintenance of Mitochondrial Function and Integrity

“…However, PINK1 or Parkin overexpression rescues the aberrant mitochondrial phenotype in DJ-1-deficient cells, but DJ-1 does not reduce the mitochondrial fragmentation induced by PINK1 deficiency. These findings suggest that DJ-1 acts independent of PINK1 and Parkin (Exner et al, 2007;Irrcher et al, 2010;Thomas et al, 2011).…”

Yeast DJ-1 superfamily members are required for diauxic-shift reprogramming and cell survival in stationary phase

“…S5). Human DJ-1 has been previously associated with autophagy, but its precise role is controversial (35)(36)(37). Although no association between members of the Hsp31 minifamily and RNA metabolism has been described, human DJ-1 is an RNA binding protein (38), suggesting this cellular function may be conserved.…”

The role of protein clearance mechanisms in organismal ageing and age-related diseases

“…Consequently, the irreversible binding of mutant a-synuclein to the lysosome blocks the binding of other substrates, resulting in a general impairment of the CMA pathway and further a-synuclein accumulation 110 . Proteins related to familiar PD, such as DJ-1 or LRRK2, significantly alter autophagy 111,112 .…”