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PLoS One. 2014 Mar 3;9(3):e90803. doi: 10.1371/journal.pone.0090803. eCollection 2014.

ER stress-induced eIF2-alpha phosphorylation underlies sensitivity of striatal neurons to pathogenic huntingtin.

Author information

1
Department of Cell Research and Immunology, George Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel; Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.
2
Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel; Department of Neurobiology, George Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
3
Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Martinsried, Germany.

Abstract

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 eIF2α, a stress-induced process that interferes with general protein synthesis and also induces differential translation of pro-apoptotic factors. EIF2α 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 eIF2α phosphorylation by increasing the activity of PKR-like ER-localized eIF2α 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 eIF2α phosphorylation status by pathogenic huntingtin appears to be an important cause of striatal cell death. A dephosphorylated state of eIF2α 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.

PMID:
24594939
PMCID:
PMC3940916
DOI:
10.1371/journal.pone.0090803
[Indexed for MEDLINE]
Free PMC Article

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