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An inducer of VGF protects cells against ER stress-induced cell death and prolongs survival in the mutant SOD1 animal models of familial ALS.
- Source :
-
PloS one [PLoS One] 2010 Dec 09; Vol. 5 (12), pp. e15307. Date of Electronic Publication: 2010 Dec 09. - Publication Year :
- 2010
-
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.
- Subjects :
- Aniline Compounds pharmacology
Animals
Cell Death
Cell Survival
Disease Models, Animal
Disease Progression
Humans
Mice
Mice, Transgenic
Oligonucleotide Array Sequence Analysis
Piperazines pharmacology
Superoxide Dismutase-1
Vascular Endothelial Growth Factor A metabolism
Amyotrophic Lateral Sclerosis genetics
Endoplasmic Reticulum metabolism
Mutation
Superoxide Dismutase genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 5
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 21151573
- Full Text :
- https://doi.org/10.1371/journal.pone.0015307