title: The role of SIGMAR1 gene mutation and mitochondrial dysfunction in amyotrophic lateral sclerosis.
abstract: Amyotrophic lateral sclerosis (ALS) patients exhibit diverse pathologies such as endoplasmic reticulum (ER) stress and mitochondrial dysfunction in motor neurons. Five to ten percent of patients have familial ALS, a form of the disease caused by mutations in ALS-related genes, while sporadic forms of the disease occur in 90-95% of patients. Recently, it was reported that familial ALS patients exhibit a missense mutation in SIGMAR1 (c.304G > C), which encodes sigma-1 receptor (Sig-1R), substituting glutamine for glutamic acid at amino acid residue 102 (p.E102Q). Expression of that mutant Sig-1R(E102Q) protein reduces mitochondrial ATP production, inhibits proteasome activity and causes mitochondrial injury, aggravating ER stress-induced neuronal death in neuro2A cells. In this issue, we discuss mechanisms underlying mitochondrial impairment seen in ALS motor neurons and propose that therapies that protect mitochondria might improve the quality of life (QOL) of ALS patients and should be considered for clinical trials.
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan. Electronic address: kfukunaga@m.tohoku.ac.jp.
authors.forename: Kohji
authors.initials: K
authors.lastname: Fukunaga
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan.
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Shinoda
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Tagashira
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology*; D008954:Models, Biological; D009046:Motor Neurons / Q000378:metabolism; D009154:Mutation; D018696:Neuroprotective Agents / Q000819:agonists / Q000627:therapeutic use; D017480:Receptors, sigma / Q000235:genetics* / Q000378:metabolism; D000097605:Sigma-1 Receptor
chemical_list: D018696:Neuroprotective Agents; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor
keywords: Amyotrophic lateral sclerosis; Energy production; Mitochondrial injury; SIGMAR1; TDP-43