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

Nirit Lev; Yael Barhum; Itay Lotan; Israel Steiner; Daniel Offen

doi:10.1371/journal.pone.0117190

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.

Authors

Nirit Lev¹, Yael Barhum², Itay Lotan³, Israel Steiner³, Daniel Offen²

Affiliations

¹ Neuroscience Laboratory, Felsenstein Medical Research Center, Tel Aviv University, Petah Tikva, Israel; Department of Neurology, Rabin Medical Center, Tel Aviv University, Petah Tikva, Israel.
² Neuroscience Laboratory, Felsenstein Medical Research Center, Tel Aviv University, Petah Tikva, Israel.
³ Department of Neurology, Rabin Medical Center, Tel Aviv University, Petah Tikva, Israel.

Abstract

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

Substances

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

Grants and funding

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) (http://www.isf.org.il/english/path.asp?path_id=12). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.