An Inducer of VGF protects cells against ER stress-induced cell death and prolongs survival in the mutant SOD1 animal Models of Familial ALS

Masamitsu Shimazawa, Hirotaka Tanaka, Yasushi Ito, Nobutaka Morimoto, Kazuhiro Tsuruma, Michinori Kadokura, Shigeki Tamura, Teruyoshi Inoue, Mitsunori Yamada, Hitoshi Takahashi, Hitoshi Warita, Masashi Aoki, Hideaki Hara

Research output: Contribution to journalArticlepeer-review

42 Citations (Scopus)

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.

Original languageEnglish
Article numbere15307
JournalPloS one
Volume5
Issue number12
DOIs
Publication statusPublished - 2010

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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