DJ-1 forms complexes with mutant SOD1 and ameliorates its toxicity.
Mutations in Cu/Zn superoxide dismutase (SOD1) gene cause familial amyotrophic lateral sclerosis (ALS), which could be attributed to the toxic properties of the misfolded protein, oxidative stress, and mitochondrial dysfunction. DJ-1 - a causative agent of familial Parkinson's disease PARK7 - is responsible for inducing antioxidative reaction. In this study, we showed the up-regulation of DJ-1 protein levels in mutant SOD1 transgenic mice through the lifespan were observed in the motor neurons. We demonstrated biochemically DJ-1 formed complexes with mutant SOD1 in the cell lysates. Furthermore, DJ-1 over-expression resulted in increased cell viability and reduced cell toxicity in mutant SOD1-transfected neuronal cells, because of improvement in apoptotic pathway and reduction in oxidative stress levels. We also evaluated DJ-1 levels in CSF collected from sporadic ALS patients and controls subjects. The CSF DJ-1 levels were significantly higher in patients with sporadic ALS than in control subjects. These results show that DJ-1 may be associated with sporadic and familial ALS pathogenesis. Therefore, insight into the effects of DJ-1 on mutant SOD1-mediated toxicity may provide a therapeutic advance for the treatment of motor neuron degeneration in ALS.
Yamashita
Satoshi
S
Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Honjo, Kumamoto, Japan. y-stsh@kumamoto-u.ac.jp
Mori
Akira
A
Kimura
En
E
Mita
Shuji
S
Maeda
Yasushi
Y
Hirano
Teruyuki
T
Uchino
Makoto
M
D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D046911:Macromolecular Substances / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D009046:Motor Neurons / Q000378:metabolism; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D015513:Oncogene Proteins / Q000134:cerebrospinal fluid / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D054464:Peroxiredoxins; D011485:Protein Binding / Q000502:physiology; D000071617:Protein Deglycase DJ-1; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1; D015854:Up-Regulation / Q000502:physiology
D046911:Macromolecular Substances; D015513:Oncogene Proteins; C000606290:SOD1 protein, human; D054464:Peroxiredoxins; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C503466:PARK7 protein, mouse; D000071617:Protein Deglycase DJ-1