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Updated: Jun 15, 2026
High Content Screening in Neurodegenerative Diseases
Published on: January 6, 2012
DJ-1 forms complexes with mutant SOD1 and ameliorates its toxicity
Satoshi Yamashita1, Akira Mori, En Kimura
1Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Honjo, Kumamoto, Japan. y-stsh@kumamoto-u.ac.jp
Abstract:
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.
Insights
DJ-1 protein levels increase in motor neurons of mice with mutant SOD1, suggesting a role in familial and sporadic ALS. DJ-1 may offer a therapeutic target for motor neuron degeneration.
Area of Science:
- Neuroscience
- Genetics
- Biochemistry
Background:
- Mutations in the Cu/Zn superoxide dismutase (SOD1) gene are a cause of familial amyotrophic lateral sclerosis (ALS).
- Misfolded SOD1 protein, oxidative stress, and mitochondrial dysfunction contribute to ALS pathogenesis.
- DJ-1 (PARK7) is involved in antioxidative responses and linked to familial Parkinson's disease.
Purpose of the Study:
- To investigate the role of DJ-1 in mutant SOD1-mediated neurotoxicity in ALS.
- To determine if DJ-1 levels are altered in sporadic ALS patients.
Main Methods:
- Assessed DJ-1 protein levels in motor neurons of mutant SOD1 transgenic mice.
- Examined DJ-1 and mutant SOD1 interactions biochemically.
- Investigated the effects of DJ-1 overexpression on neuronal cell viability and toxicity.
- Measured DJ-1 levels in cerebrospinal fluid (CSF) from sporadic ALS patients and controls.
Main Results:
- DJ-1 protein levels were upregulated in motor neurons of mutant SOD1 mice throughout their lifespan.
- DJ-1 formed complexes with mutant SOD1 in cell lysates.
- Overexpression of DJ-1 enhanced cell viability and reduced toxicity in mutant SOD1-transfected cells by improving the apoptotic pathway and decreasing oxidative stress.
- CSF DJ-1 levels were significantly higher in sporadic ALS patients compared to controls.
Conclusions:
- DJ-1 is upregulated in the context of mutant SOD1 toxicity and may play a role in both familial and sporadic ALS pathogenesis.
- DJ-1's protective effects against mutant SOD1-mediated toxicity suggest it as a potential therapeutic target for ALS treatment.
- Further research into DJ-1's mechanisms could lead to advancements in treating motor neuron degeneration.
