A mutation in the chaperone {sigma}1-receptor impairs mitochondrial ATP production in amyotrophic lateral sclerosis [Molecular Bases of Disease]

December 12th, 2013 by Tagashira, H., Shioda, N., Fukunaga, K.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder caused by motor neuron dysfunction. Recently, a E102Q mutation in the chaperone protein σ1R (σ1RE102Q) was discovered in familial ALS patients. Here, we address mechanisms underlying neurodegeneration caused by this mutation using overexpression analysis in Neuro2A cells. σ1RE102Q overexpression promoted its dissociation from the endoplasmic reticulum (ER) membrane and its cytoplasmic aggregation, and in turn impaired mitochondrial ATP production. Under ER stress conditions, overexpression of wild-type σ1R suppressed ER stress-induced mitochondrial injury, whereas σ1RE102Q overexpression dramatically aggravated those activities, inducing autophagic cell death. Moreover, aberrant extra-nuclear localization of the TAR DNA-binding protein 43 (TDP-43) was observed in σ1RE102Q-overexpressing cells, a condition exacerbated by ER stress. Treatment of cells with the mitochondrial Ca2+ transporter inhibitor Ru360 mimicked the effects of σ1RE102Q overexpression, indicating that impairment of σ1R-mediated mitochondrial Ca2+ transport likely underlies TDP-43 extra-nuclear localization, segregation in inclusion bodies, and ubiquitination. Finally, enhanced ATP production promoted by 3-methylpyruvate treatment rescued TDP-43 extra-nuclear localization caused by σ1RE102Q overexpression. Taken together, phenotypes observed in σ1RE102Q-overexpressing cells suggest that ATP supplementation by methyl pyruvate is potential therapeutic strategy to treat ALS caused by σ1-receptor mutations.
  • Posted in Journal of Biological Chemistry, Publications
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