ArticleHuman molecular genetics2016
Huntingtin N17 domain is a reactive oxygen species sensor regulating huntingtin phosphorylation and localization.
Article in Human molecular genetics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 67 citations in OpenAlex.
- Transient Interdomain Interactions Modulate the Monomeric Structural Ensemble and Self-Assembly of Huntingtin Exon 1.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Roscovitine, a CDK Inhibitor, Reduced Neuronal Toxicity of mHTT by Targeting HTT Phosphorylation at S1181 and S1201 In Vitro.International journal of molecular sciences · 2024Article
- Poly ADP-ribose signaling is dysregulated in Huntington disease.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Neuropathogenesis-on-chips for neurodegenerative diseases.Nature communications · 2024Review
- Redox dysregulation as a driver for DNA damage and its relationship to neurodegenerative diseases.Translational neurodegeneration · 2023Review
- Pathogenesis and potential therapeutic application of stem cells transplantation in Huntington's disease.Regenerative therapy · 2022Review
- Oxidation Promotes Distinct Huntingtin Aggregates in the Presence and Absence of Membranes.Biochemistry · 2022Article
- Recent Microscopy Advances and the Applications to Huntington's Disease Research.Journal of Huntington's disease · 2022Review
- Site-Specific Phosphorylation of Huntingtin Exon 1 Recombinant Proteins Enabled by the Discovery of Novel Kinases.Chembiochem : a European journal of chemical biology · 2021Article
- Characterization of a Knock-In Mouse Model with a Huntingtin Exon 1 Deletion.Journal of Huntington's disease · 2021Article
- Investigating Crosstalk Among PTMs Provides Novel Insight Into the Structural Basis Underlying the Differential Effects of Nt17 PTMs on Mutant Httex1 Aggregation.Frontiers in molecular biosciences · 2021Article
- Reactive Species in Huntington Disease: Are They Really the Radicals You Want to Catch?Antioxidants (Basel, Switzerland) · 2020Review
- Exploring the role of high-mobility group box 1 (HMGB1) protein in the pathogenesis of Huntington's disease.Journal of molecular medicine (Berlin, Germany) · 2020Review
- The Interaction of Aging and Cellular Stress Contributes to Pathogenesis in Mouse and Human Huntington Disease Neurons.Frontiers in aging neuroscience · 2020Article
- PGC-1α, Sirtuins and PARPs in Huntington's Disease and Other Neurodegenerative Conditions: NAD+ to Rule Them All.Neurochemical research · 2019Review
- Structure of Membrane-Bound Huntingtin Exon 1 Reveals Membrane Interaction and Aggregation Mechanisms.Structure (London, England : 1993) · 2019Article
- DNA Damage Repair in Huntington's Disease and Other Neurodegenerative Diseases.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2019Review
- High-mobility group box 1 links sensing of reactive oxygen species by huntingtin to its nuclear entry.The Journal of biological chemistry · 2019Article
- The Role of Post-translational Modifications on the Energy Landscape of Huntingtin N-Terminus.Frontiers in molecular biosciences · 2019Article
- Targeting N-Terminal Huntingtin with a Dual-sgRNA Strategy by CRISPR/Cas9.BioMed research international · 2019Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
The N17 domain of the huntingtin protein is post-translationally modified and is the master regulator of huntingtin intracellular localization. In Huntington's disease (HD), mutant huntingtin is hypo-phosphorylated at serines 13 and 16 within N17, and increasing N17 phosphorylation has been shown to be protective in HD mouse models. Thus, N17 phosphorylation is defined as a sub-target of huntingtin for potential therapeutic intervention. We have previously shown that cellular stress can affect huntingtin nuclear entry and phosphorylation. Here, we demonstrate that huntingtin localization can be specifically affected by reactive oxygen species (ROS) stress. We have located the sensor of this stress to the N17 domain, specifically to a highly conserved methionine at position 8. In vitro, we show by circular dichroism spectroscopy structural studies that the alpha-helical structure of N17 changes in response to redox conditions and show that the consequence of this change is enhanced N17 phosphorylation and nuclear targeting of endogenous huntingtin. Using N17 substitution point mutants, we demonstrate that N17 sulphoxidation enhances N17 dissociation from the endoplasmic reticulum (ER) membrane. This enhanced solubility makes N17 a better substrate for phosphorylation and subsequent nuclear retention. This ability of huntingtin to sense ROS levels at the ER, with phosphorylation and nuclear localization as a response, suggests that ROS stress due to aging could be a critical molecular trigger of huntingtin functions and dysfunctions in HD and may explain the age-onset nature of the disorder.
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