| First Author | Wang L | Year | 2014 |
| Journal | Hum Mol Genet | Volume | 23 |
| Issue | 10 | Pages | 2629-38 |
| PubMed ID | 24368417 | Mgi Jnum | J:209060 |
| Mgi Id | MGI:5565622 | Doi | 10.1093/hmg/ddt658 |
| Citation | Wang L, et al. (2014) An enhanced integrated stress response ameliorates mutant SOD1-induced ALS. Hum Mol Genet 23(10):2629-38 |
| abstractText | Varied stresses to cells can lead to a repression in translation by triggering phosphorylation of eukaryotic translation initiator factor 2alpha (eIF2alpha), which is central to a process known as the integrated stress response (ISR). PKR-like ER-localized eIF2 kinase (PERK), one of the kinases that phosphorylates eIF2alpha and coordinates the ISR, is activated by stress occurring from the accumulation of misfolded or unfolded proteins in the endoplasmic reticulum (ER). Mutant Cu/Zn superoxide dismutase (mtSOD1) is thought to cause familial amyotrophic lateral sclerosis (FALS) because it misfolds and aggregates. Published studies have suggested that ER stress is involved in FALS pathogenesis since mtSOD1 accumulates inside the ER and activates PERK leading to phosphorylated eIF2alpha (p-eIF2alpha). We previously used a genetic approach to show that haploinsufficiency of PERK significantly accelerates disease onset and shortens survival of G85R mtSOD1 FALS transgenic mice. We now show that G85R mice that express reduced levels of active GADD34, which normally dephosphorylates p-eIF2alpha and allows recovery from the global suppression of protein synthesis, markedly ameliorates disease. These studies emphasize the importance of the ISR, and specifically the PERK pathway, in the pathogenesis of mtSOD1-induced FALS and as a target for treatment. Furthermore, the ISR may be an appropriate therapeutic target for sporadic ALS and other neurodegenerative diseases since misfolded proteins have been implicated in these disorders. |
