Cargando…

ER Stress-Induced eIF2-alpha Phosphorylation Underlies Sensitivity of Striatal Neurons to Pathogenic Huntingtin

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-ind...

Descripción completa

Detalles Bibliográficos
Autores principales: Leitman, Julia, Barak, Boaz, Benyair, Ron, Shenkman, Marina, Ashery, Uri, Hartl, F. Ulrich, Lederkremer, Gerardo Z.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3940916/
https://www.ncbi.nlm.nih.gov/pubmed/24594939
http://dx.doi.org/10.1371/journal.pone.0090803
_version_ 1782305835227021312
author Leitman, Julia
Barak, Boaz
Benyair, Ron
Shenkman, Marina
Ashery, Uri
Hartl, F. Ulrich
Lederkremer, Gerardo Z.
author_facet Leitman, Julia
Barak, Boaz
Benyair, Ron
Shenkman, Marina
Ashery, Uri
Hartl, F. Ulrich
Lederkremer, Gerardo Z.
author_sort Leitman, Julia
collection PubMed
description 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.
format Online
Article
Text
id pubmed-3940916
institution National Center for Biotechnology Information
language English
publishDate 2014
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-39409162014-03-06 ER Stress-Induced eIF2-alpha Phosphorylation Underlies Sensitivity of Striatal Neurons to Pathogenic Huntingtin Leitman, Julia Barak, Boaz Benyair, Ron Shenkman, Marina Ashery, Uri Hartl, F. Ulrich Lederkremer, Gerardo Z. PLoS One Research Article 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. Public Library of Science 2014-03-03 /pmc/articles/PMC3940916/ /pubmed/24594939 http://dx.doi.org/10.1371/journal.pone.0090803 Text en © 2014 Leitman et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Leitman, Julia
Barak, Boaz
Benyair, Ron
Shenkman, Marina
Ashery, Uri
Hartl, F. Ulrich
Lederkremer, Gerardo Z.
ER Stress-Induced eIF2-alpha Phosphorylation Underlies Sensitivity of Striatal Neurons to Pathogenic Huntingtin
title ER Stress-Induced eIF2-alpha Phosphorylation Underlies Sensitivity of Striatal Neurons to Pathogenic Huntingtin
title_full ER Stress-Induced eIF2-alpha Phosphorylation Underlies Sensitivity of Striatal Neurons to Pathogenic Huntingtin
title_fullStr ER Stress-Induced eIF2-alpha Phosphorylation Underlies Sensitivity of Striatal Neurons to Pathogenic Huntingtin
title_full_unstemmed ER Stress-Induced eIF2-alpha Phosphorylation Underlies Sensitivity of Striatal Neurons to Pathogenic Huntingtin
title_short ER Stress-Induced eIF2-alpha Phosphorylation Underlies Sensitivity of Striatal Neurons to Pathogenic Huntingtin
title_sort er stress-induced eif2-alpha phosphorylation underlies sensitivity of striatal neurons to pathogenic huntingtin
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3940916/
https://www.ncbi.nlm.nih.gov/pubmed/24594939
http://dx.doi.org/10.1371/journal.pone.0090803
work_keys_str_mv AT leitmanjulia erstressinducedeif2alphaphosphorylationunderliessensitivityofstriatalneuronstopathogenichuntingtin
AT barakboaz erstressinducedeif2alphaphosphorylationunderliessensitivityofstriatalneuronstopathogenichuntingtin
AT benyairron erstressinducedeif2alphaphosphorylationunderliessensitivityofstriatalneuronstopathogenichuntingtin
AT shenkmanmarina erstressinducedeif2alphaphosphorylationunderliessensitivityofstriatalneuronstopathogenichuntingtin
AT asheryuri erstressinducedeif2alphaphosphorylationunderliessensitivityofstriatalneuronstopathogenichuntingtin
AT hartlfulrich erstressinducedeif2alphaphosphorylationunderliessensitivityofstriatalneuronstopathogenichuntingtin
AT lederkremergerardoz erstressinducedeif2alphaphosphorylationunderliessensitivityofstriatalneuronstopathogenichuntingtin