title: Methyl pyruvate rescues mitochondrial damage caused by SIGMAR1 mutation related to amyotrophic lateral sclerosis.
abstract: BACKGROUND
  Amyotrophic lateral sclerosis (ALS) is a disease caused by motor neuron degeneration. Recently, a novel SIGMAR1 gene variant (p.E102Q) was discovered in some familial ALS patients.
  
  
  METHODS
  We address mechanisms underlying neurodegeneration caused by the mutation using Neuro2A cells overexpressing σ1R(E102Q), a protein of a SIGMAR1 gene variant (p.E102Q) and evaluate potential amelioration by ATP production via methyl pyruvate (MP) treatment.
  
  
  RESULTS
  σ1R(E102Q) overexpression promoted dissociation of the protein from the endoplasmic reticulum (ER) membrane and cytoplasmic aggregation, which in turn impaired mitochondrial ATP production and proteasome activity. Under ER stress conditions, overexpression of wild-type σ1R suppressed ER stress-induced mitochondrial injury, whereas σ1R(E102Q) overexpression aggravated mitochondrial damage and induced autophagic cell death. Moreover, σ1R(E102Q)-overexpressing cells showed aberrant extra-nuclear localization of the TAR DNA-binding protein (TDP-43), a condition exacerbated by ER stress. Treatment of cells with the mitochondrial Ca(2+) transporter inhibitor Ru360 mimicked the effects of σ1R(E102Q) overexpression, indicating that aberrant σ1R-mediated mitochondrial Ca(2+) transport likely underlies TDP-43 extra-nuclear localization, segregation in inclusion bodies, and ubiquitination. Finally, enhanced ATP production promoted by methyl pyruvate (MP) treatment rescued proteasome impairment and TDP-43 extra-nuclear localization caused by σ1R(E102Q) overexpression.
  
  
  CONCLUSIONS
  Our observations suggest that neurodegeneration seen in some forms of ALS are due in part to aberrant mitochondrial ATP production and proteasome activity as well as TDP-43 mislocalization resulting from the SIGMAR1 mutation.
  
  
  CONCLUSIONS
  ATP supplementation by MP represents a potential therapeutic strategy to treat ALS caused by SIGMAR1 mutation.
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-ku, Sendai, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Tagashira
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-ku, Sendai, Japan.
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Shinoda
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-ku, Sendai, Japan.
authors.forename: Norifumi
authors.initials: N
authors.lastname: Shioda
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-ku, Sendai, Japan. Electronic address: kfukunaga@m.tohoku.ac.jp.
authors.forename: Kohji
authors.initials: K
authors.lastname: Fukunaga
keywords: Amyotrophic lateral sclerosis; Autophagy; Endoplasmic reticulum stress; Neurodegeneration; Sigma-1 receptor