ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2010
Aberrant Rab11-dependent trafficking of the neuronal glutamate transporter EAAC1 causes oxidative stress and cell death in Huntington's disease.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 100 papers.
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100 citing papers in PubMed, 166 citations in OpenAlex.
- Oxidative stress and inflammation in neurodegenerative disorders.Archives of toxicology · 2026Review
- The SLC7A11 Thermostat: A Molecular Signaling Switch Between Ferroptosis and Disulfidptosis in Neurodegenerative Disease.Molecular neurobiology · 2026Review
- Sulfur-Containing Amino Acid Homeostasis in the Central Nervous System: From Physiology Regulation to Metal-Induced Neurotoxicity.Metabolites · 2026Review
- Huntingtin and its allies at the cortico-striatal synapse.Cell death & disease · 2026Review
- Hydrogen Sulfide Signaling in Neurodegenerative Movement Disorders.Handbook of experimental pharmacology · 2026Review
- Rab11a-dependent recycling of Glut3 inhibits seizure-induced neuronal disulfidptosis by alleviating glucose deficiency.Cell & bioscience · 2025Article
- A collaborative network analysis for the interpretation of transcriptomics data in Huntington's disease.Scientific reports · 2025Article
- Endosomal traffic disorders: a driving force behind neurodegenerative diseases.Translational neurodegeneration · 2024Review
- Article
- Defects in Glutathione System in an Animal Model of Amyotrophic Lateral Sclerosis.Antioxidants (Basel, Switzerland) · 2023Article
- Crosstalk between the Rho and Rab family of small GTPases in neurodegenerative disorders.Frontiers in cellular neuroscience · 2023Review
- Mechanisms Underlying Neurodegenerative Disorders and Potential Neuroprotective Activity of Agrifood By-Products.Antioxidants (Basel, Switzerland) · 2022Review
- A Novel Huntington's Disease Assessment Platform to Support Future Drug Discovery and Development.International journal of molecular sciences · 2022Article
- Impaired XK recycling for importing manganese underlies striatal vulnerability in Huntington's disease.The Journal of cell biology · 2022Article
- Mutant Huntingtin Derails Cysteine Metabolism in Huntington's Disease at Both Transcriptional and Post-Translational Levels.Antioxidants (Basel, Switzerland) · 2022Article
- Cysteine metabolism and hydrogen sulfide signaling in Huntington's disease.Free radical biology & medicine · 2022Review
- Therapeutic Targeting of Rab GTPases: Relevance for Alzheimer's Disease.Biomedicines · 2022Review
- Trappc9 Deficiency Impairs the Plasticity of Stem Cells.International journal of molecular sciences · 2022Article
- Nuclear and Cytoplasmatic Players in Mitochondria-Related CNS Disorders: Chromatin Modifications and Subcellular Trafficking.Biomolecules · 2022Review
- Signaling Overlap between the Golgi Stress Response and Cysteine Metabolism in Huntington's Disease.Antioxidants (Basel, Switzerland) · 2021Review
40 more citing papers are in PubMed but not listed here.
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Authors and funding
9 authors at 3 institutions in 1 country.
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Abstract
Oxidative stress contributes to neurodegeneration in Huntington's disease (HD). However, the origins of oxidative stress in HD remain unclear. Studies in HD transgenic models suggest involvement of mitochondrial dysfunction, which would lead to overproduction of reactive oxygen species (ROS). Impaired mitochondria complexes occur in late stages of HD but not in presymptomatic or early-stage HD patients. Thus, other mechanisms may account for the earliest source of oxidative stress caused by endogenous mutant huntingtin. Here, we report that decreased levels of a major intracellular antioxidant glutathione coincide with accumulation of ROS in primary HD neurons prepared from embryos of HD knock-in mice (HD(140Q/140Q)), which have human huntingtin exon 1 with 140 CAG repeats inserted into the endogenous mouse huntingtin gene. Uptake of extracellular cysteine through the glutamate/cysteine transporter EAAC1 is required for de novo synthesis of glutathione in neurons. We found that, compared with wild-type neurons, HD neurons had lower cell surface levels of EAAC1 and were deficient in taking up cysteine. Constitutive trafficking of EAAC1 from recycling endosomes relies on Rab11 activity, which is defective in the brain of HD(140Q/140Q) mice. Enhancement of Rab11 activity by expression of a dominant-active Rab11 mutant in primary HD neurons ameliorated the deficit in cysteine uptake, increased levels of intracellular glutathione, normalized clearance of ROS, and improved neuronal survival. Our data support a novel mechanism for oxidative stress in HD: Rab11 dysfunction slows trafficking of EAAC1 to the cell surface and impairs cysteine uptake, thereby leading to deficient synthesis of glutathione.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.