TY - JOUR
T1 - The role of SIGMAR1 gene mutation and mitochondrial dysfunction in amyotrophic lateral sclerosis
AU - Fukunaga, Kohji
AU - Shinoda, Yasuharu
AU - Tagashira, Hideaki
N1 - Funding Information:
This work was supported in part by grants-in-aid for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan (KAKENHI 24102505 , 24659024 and 25293124 to K.F.), a Grant-in-Aid for Development of Systems and Technology for Advanced Measurement and Analysis from the Japan Science and Technology Agency (JST) (K.F.).
Publisher Copyright:
© 2015 Japanese Pharmacological Society.
PY - 2015/1
Y1 - 2015/1
N2 - 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-1RE102Q 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.
AB - 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-1RE102Q 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.
KW - Amyotrophic lateral sclerosis
KW - Energy production
KW - Mitochondrial injury
KW - SIGMAR1
KW - TDP-43
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U2 - 10.1016/j.jphs.2014.12.012
DO - 10.1016/j.jphs.2014.12.012
M3 - Review article
C2 - 25704016
AN - SCOPUS:84924072040
VL - 127
SP - 36
EP - 41
JO - Journal of Pharmacological Sciences
JF - Journal of Pharmacological Sciences
SN - 1347-8648
IS - 1
ER -