ArticlePloS one2014
ER stress-induced eIF2-alpha phosphorylation underlies sensitivity of striatal neurons to pathogenic huntingtin.
Article in PloS one, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers.
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52 citing papers in PubMed, 97 citations in OpenAlex.
- Inhibition of the mitochondrial pyruvate carrier attenuates the integrated stress response activation in a cellular model of Huntington's disease.Molecular and cellular biochemistry · 2026Article
- Distinct molecular patterns in R6/2 HD mouse brain: Insights from spatiotemporal transcriptomics.Neuron · 2025Article
- Sigma 1 Receptor and Its Pivotal Role in Neurological Disorders.ACS pharmacology & translational science · 2025Review
- Long non-coding RNA-mediated modulation of endoplasmic reticulum stress under pathological conditions.Journal of cellular and molecular medicine · 2024Review
- Endoplasmic reticulum stress and therapeutic strategies in metabolic, neurodegenerative diseases and cancer.Molecular medicine (Cambridge, Mass.) · 2024Review
- Longitudinal modeling of human neuronal aging reveals the contribution of the RCAN1-TFEB pathway to Huntington's disease neurodegeneration.Nature aging · 2024Article
- Endoplasmic Reticulum Stress and Its Impact on Adipogenesis: Molecular Mechanisms Implicated.Nutrients · 2023Review
- Gelation of cytoplasmic expanded CAG RNA repeats suppresses global protein synthesis.Nature chemical biology · 2023Article
- Role of Nanoparticle-Conjugates and Nanotheranostics in Abrogating Oxidative Stress and Ameliorating Neuroinflammation.Antioxidants (Basel, Switzerland) · 2023Review
- From Pathogenesis to Therapeutics: A Review of 150 Years of Huntington's Disease Research.International journal of molecular sciences · 2023Review
- IGF/mTORC1/S6 Signaling Is Potentiated and Prolonged by Acute Loading of Subtoxicological Manganese Ion.Biomolecules · 2023Article
- The PERK pathway: beneficial or detrimental for neurodegenerative diseases and tumor growth and cancer.Human molecular genetics · 2023Review
- Cell Rearrangement and Oxidant/Antioxidant Imbalance in Huntington's Disease.Antioxidants (Basel, Switzerland) · 2023Review
- Potential roles of the endoplasmic reticulum stress pathway in amyotrophic lateral sclerosis.Frontiers in aging neuroscience · 2023Review
- Protein quality control and aggregation in the endoplasmic reticulum: From basic to bedside.Frontiers in cell and developmental biology · 2023Review
- Impaired Restoration of Global Protein Synthesis Contributes to Increased Vulnerability to Acute ER Stress Recovery in Huntington's Disease.Cellular and molecular neurobiology · 2022Article
- Age-related Huntington's disease progression modeled in directly reprogrammed patient-derived striatal neurons highlights impaired autophagy.Nature neuroscience · 2022Article
- Mid1 is associated with androgen-dependent axonal vulnerability of motor neurons in spinal and bulbar muscular atrophy.Cell death & disease · 2022Article
- The Common Cellular Events in the Neurodegenerative Diseases and the Associated Role of Endoplasmic Reticulum Stress.International journal of molecular sciences · 2022Review
- Impact of ER Stress and ER-Mitochondrial Crosstalk in Huntington's Disease.International journal of molecular sciences · 2022Review
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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