title: ER stress-induced eIF2-alpha phosphorylation underlies sensitivity of striatal neurons to pathogenic huntingtin.
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.
authors.affiliation: 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.
authors.forename: Julia
authors.initials: J
authors.lastname: Leitman
authors.affiliation: 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.
authors.forename: Boaz
authors.initials: B
authors.lastname: Barak
authors.affiliation: 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.
authors.forename: Ron
authors.initials: R
authors.lastname: Benyair
authors.affiliation: 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.
authors.forename: Marina
authors.initials: M
authors.lastname: Shenkman
authors.affiliation: 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.
authors.forename: Uri
authors.initials: U
authors.lastname: Ashery
authors.affiliation: Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Martinsried, Germany.
authors.forename: F Ulrich
authors.initials: FU
authors.lastname: Hartl
authors.affiliation: 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.
authors.forename: Gerardo Z
authors.initials: GZ
authors.lastname: Lederkremer
mesh_terms: D000818:Animals; D017931:DNA Primers / Q000235:genetics; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005822:Genetic Vectors / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D000071058:Huntingtin Protein; D015151:Immunoblotting; D051379:Mice; D041681:NIH 3T3 Cells; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014793:Visual Cortex / Q000166:cytology*
chemical_list: D017931:DNA Primers; D015852:Eukaryotic Initiation Factor-2; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; C531557:eIF2alpha kinase, mouse