DJ-1 knockout augments disease severity and shortens survival in a mouse model of ALS

PLoS One. 2015 Mar 30;10(3):e0117190. doi: 10.1371/journal.pone.0117190. eCollection 2015.


Amyotrophic lateral sclerosis (ALS) is a progressive, lethal, neurodegenerative disorder, characterized by the degeneration of motor neurons. Oxidative stress plays a central role in the disease progression, in concert with an enhanced glutamate excitotoxicity and neuroinflammation. DJ-1 mutations, leading to the loss of functional protein, cause familial Parkinson's disease and motor neuron disease in several patients. DJ-1 responds to oxidative stress and plays an important role in the cellular defense mechanisms. We aimed to investigate whether loss of functional DJ-1 alters the disease course and severity in an ALS mouse model. To this end we used mice that express the human SOD1G93A mutation, the commonly used model of ALS and knockout of DJ-1 mice to generate SOD1 DJ-1 KO mice. We found that knocking out DJ-1in the ALS model led to an accelerated disease course and shortened survival time. DJ-1 deficiency was found to increase neuronal loss in the spinal cord associated with increased gliosis in the spinal cord and reduced antioxidant response that was regulated by the Nrf2 mechanism.The importance of DJ-1 in ALS was also illustrated in a motor neuron cell line that was exposed to glutamate toxicity and oxidative stress. Addition of the DJ-1 derived peptide, ND-13, enhanced the resistance to glutamate and SIN-1 induced toxicity. Thus, our results maintain that DJ-1 plays a role in the disease process and promotes the necessity of further investigation of DJ-1 as a therapeutic target for ALS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / diagnosis
  • Amyotrophic Lateral Sclerosis / genetics*
  • Amyotrophic Lateral Sclerosis / mortality
  • Animals
  • Cell Line
  • Cell Survival / genetics
  • Disease Models, Animal
  • Female
  • Gliosis / genetics
  • Glutamic Acid / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins / chemistry
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Motor Neurons / drug effects
  • Motor Neurons / metabolism
  • Mutation
  • NF-E2-Related Factor 2 / metabolism
  • Oncogene Proteins / chemistry
  • Oncogene Proteins / genetics*
  • Oncogene Proteins / metabolism
  • Peptides / metabolism
  • Peptides / pharmacology
  • Protein Deglycase DJ-1
  • Severity of Illness Index
  • Spinal Cord / metabolism
  • Spinal Cord / pathology
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase-1


  • Intracellular Signaling Peptides and Proteins
  • NF-E2-Related Factor 2
  • Oncogene Proteins
  • Peptides
  • SOD1 protein, human
  • Glutamic Acid
  • Sod1 protein, mouse
  • Superoxide Dismutase
  • Superoxide Dismutase-1
  • PARK7 protein, human
  • Protein Deglycase DJ-1

Grant support

This research was supported by funding from UGH Pharma and the Lagacy Heritage Clinical Research Initiative of the Israel Science Foundation (grant 1690/09 to NL) ( The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.