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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.
Highlights
In chronic neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS), abnormally unfolded proteins are known to aggregate and accumulate in neurons, and these proteins are thought to be closely related to the initiation and development of these neurodegenerative diseases [1,2,3]
These data suggest that the protective effects of SUN N8075 on endoplasmic reticulum (ER) stress-induced cell death are mediated by a mechanism other than antioxidant effect
SUN N8075 and antioxidants both inhibited the reduction of cell viability in mouse neuronal precursor cells (RGC-5) after serum deprivation or intrinsic oxidative stress induced by L-buthionine-(S,R)-sulfoximine (BSO) plus glutamate, suggesting that SUN N8075 protected cell damage against other stresses depending on the antioxidative effect (Fig. S2)
Summary
In chronic neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS), abnormally unfolded proteins are known to aggregate and accumulate in neurons, and these proteins are thought to be closely related to the initiation and development of these neurodegenerative diseases [1,2,3]. We demonstrated that SUN N8075 induces VGF nerve growth factor inducible (VGF) as a mechanism for protecting ER stressinduced cell death in an antioxidant-independent manner. A recent study reported that VGF content was decreased in the cerebrospinal fluid (CSF) of ALS patients and in the serum, CSF and spinal cord motor neurons of G93A mice [13]. These findings strongly suggest that a VGF inducer, SUN N8075, may become a potential therapeutic candidate for ALS. We demonstrated that (i) VGF is involved in the protective effects of SUN N8075 on ER stress-induced cell death and (ii) SUN N8075 protects against disease progression and prolongs survival in familial ALS models involving ER stress
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