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.
Highlights
A so far unexplained phenomenon in many neurodegenerative diseases is the high sensitivity of certain specific cell types of the central nervous system
Given that mutant Htt induces endoplasmic reticulum (ER) stress [7,8,9,10], we investigated how striatal cells handle the stress compared to other cell types
Following 1h of Tun or MG-132 treatments, early unfolded protein response (UPR) activation, as revealed by the phosphorylated levels of the translation initiation factor eIF2a and of its kinase PKRlike ER-localized eIF2a kinase (PERK), was unusually low in STHdhQ7/7 and increased in STHdhQ111/ 111 cells, comparable to the levels induced in murine NIH 3T3 fibroblasts (Fig. 1A-D)
Summary
A so far unexplained phenomenon in many neurodegenerative diseases is the high sensitivity of certain specific cell types of the central nervous system. HD is a progressive, fatal genetic disorder affecting cognition and movement, which arises from mutant forms of the huntingtin (Htt) protein with expanded polyglutamine (polyQ) tracts (.35 amino acids) This mutation causes Htt aggregation, which interferes with normal cell metabolism [4,5,6], leading to cytotoxicity through a yet unclear mechanism. Striatal cells showed a much lower level of eIF2a phosphorylation than other cell types, which was much increased by pathogenic Htt expression This was true when analyzing the striatum compared to other regions in murine brain sections. We exploited this phenotype of striatal neurons by inhibiting the PERK pathway, compensating for the toxic effect of polyQ-expanded Htt
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