Familial amyotrophic lateral sclerosis (FALS) -linked SOD1 mutation accelerates neuronal cell death by activating cleavage of caspase-4 under ER stress in an in vitro model of FALS
Koyama, Y.; Hiratsuka, T.; Matsuzaki, S.; Yamagishi, S.; Kato, S.; Katayama, T.; Tohyama, M.
Neurochemistry International 57(7): 838-843
ISSN/ISBN: 1872-9754 PMID: 20816908 DOI: 10.1016/j.neuint.2010.08.023
Recently, endoplasmic reticulum (ER) dysfunction has been implicated in the pathogenesis of familial amyotrophic lateral sclerosis (FALS). Although up-regulation of caspase-12 has been reported in G93A SOD1 transgenic mice, it is controversial whether similar mechanisms operate in human FALS. We found that ER stress in cells stably expressing L84V SOD1 induces neuronal cell death and accelerates cleavage of caspase-4. We also detected oligomer formation of L84V SOD1 in L84V SOD1-expressing human neuroblastoma cells. These findings show that ER stress in L84V SOD1-expressing human cells causes the aggregation and inclusion bodies of L84V SOD1 to induce neuronal death through the accelerated cleavage of caspase-4.