title: An inducer of VGF protects cells against ER stress-induced cell death and prolongs survival in the mutant SOD1 animal models of familial ALS.
abstract: Amyotrophic lateral sclerosis (ALS) is the most frequent adult-onset motor neuron disease, and recent evidence has suggested that endoplasmic reticulum (ER) stress signaling is involved in the pathogenesis of ALS. Here we identified a small molecule, SUN N8075, which has a marked protective effect on ER stress-induced cell death, in an in vitro cell-based screening, and its protective mechanism was mediated by an induction of VGF nerve growth factor inducible (VGF): VGF knockdown with siRNA completely abolished the protective effect of SUN N8075 against ER-induced cell death, and overexpression of VGF inhibited ER-stress-induced cell death. VGF level was lower in the spinal cords of sporadic ALS patients than in the control patients. Furthermore, SUN N8075 slowed disease progression and prolonged survival in mutant SOD1 transgenic mouse and rat models of ALS, preventing the decrease of VGF expression in the spinal cords of ALS mice. These data suggest that VGF plays a critical role in motor neuron survival and may be a potential new therapeutic target for ALS, and SUN N8075 may become a potential therapeutic candidate for treatment of ALS.
authors.affiliation: Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Shimazawa
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Tanaka
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Ito
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Morimoto
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Tsuruma
authors.forename: Michinori
authors.initials: M
authors.lastname: Kadokura
authors.forename: Shigeki
authors.initials: S
authors.lastname: Tamura
authors.forename: Teruyoshi
authors.initials: T
authors.lastname: Inoue
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Yamada
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Takahashi
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Warita
authors.forename: Masashi
authors.initials: M
authors.lastname: Aoki
authors.forename: Hideaki
authors.initials: H
authors.lastname: Hara
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D016923:Cell Death; D002470:Cell Survival; D004195:Disease Models, Animal; D018450:Disease Progression; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D010879:Piperazines / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000814:Aniline Compounds; D010879:Piperazines; C000606290:SOD1 protein, human; C413884:SUN N8075; D042461:Vascular Endothelial Growth Factor A; C000606291:Sod1 protein, mouse; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1