| First Author | Leitman J | Year | 2014 |
| Journal | PLoS One | Volume | 9 |
| Issue | 3 | Pages | e90803 |
| PubMed ID | 24594939 | Mgi Jnum | J:214700 |
| Mgi Id | MGI:5603713 | Doi | 10.1371/journal.pone.0090803 |
| Citation | Leitman J, et al. (2014) ER stress-induced eIF2-alpha phosphorylation underlies sensitivity of striatal neurons to pathogenic huntingtin. PLoS One 9(3):e90803 |
| abstractText | A hallmark of Huntington's disease is the pronounced sensitivity of striatal neurons to polyglutamine-expanded huntingtin expression. Here we show that cultured striatal cells and murine brain striatum have remarkably low levels of phosphorylation of translation initiation factor eIF2alpha, a stress-induced process that interferes with general protein synthesis and also induces differential translation of pro-apoptotic factors. EIF2alpha phosphorylation was elevated in a striatal cell line stably expressing pathogenic huntingtin, as well as in brain sections of Huntington's disease model mice. Pathogenic huntingtin caused endoplasmic reticulum (ER) stress and increased eIF2alpha phosphorylation by increasing the activity of PKR-like ER-localized eIF2alpha kinase (PERK). Importantly, striatal neurons exhibited special sensitivity to ER stress-inducing agents, which was potentiated by pathogenic huntingtin. We could strongly reduce huntingtin toxicity by inhibiting PERK. Therefore, alteration of protein homeostasis and eIF2alpha phosphorylation status by pathogenic huntingtin appears to be an important cause of striatal cell death. A dephosphorylated state of eIF2alpha has been linked to cognition, which suggests that the effect of pathogenic huntingtin might also be a source of the early cognitive impairment seen in patients. |
