ArticleProceedings of the National Academy of Sciences of the United States of America2020
Site-specific ubiquitination of pathogenic huntingtin attenuates its deleterious effects.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 39 citations in OpenAlex.
- The DNA/RNA autophagy protein SIDT2 as a novel neuropathological hallmark in Huntington disease.Brain pathology (Zurich, Switzerland) · 2026Article
- PROTAC-Based Strategies in Neurodegenerative Diseases: Challenges and Perspectives.Pharmaceuticals (Basel, Switzerland) · 2026Review
- Molecular Mechanisms and Therapeutic Potential of Degron-Mediated Proteostasis Regulation in Neurodegenerative Diseases.Cellular and molecular neurobiology · 2026Review
- Prevention of ubiquitination at K6 and K9 in mutant huntingtin exacerbates disease pathology in a knock-in mouse model.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Ubiquitin signatures on aggregating proteins in neurodegeneration.Essays in biochemistry · 2025Review
- Post-Translational Modifications of Huntingtin: Mechanistic Insights and Therapeutic Opportunities in Huntington's Disease.International journal of molecular sciences · 2025Review
- Advancements in PROTAC-based therapies for neurodegenerative diseases.Future medicinal chemistry · 2025Review
- The ubiquitin-conjugating enzyme UBE2D maintains a youthful proteome and ensures protein quality control during aging by sustaining proteasome activity.PLoS biology · 2025Article
- Peripheral sequestration of huntingtin delays neuronal death and depends on N-terminal ubiquitination.Communications biology · 2024Article
- Disruption of the nascent polypeptide-associated complex leads to reduced polyglutamine aggregation and toxicity.PloS one · 2024Article
- Elucidation of Site-Specific Ubiquitination on Chaperones in Response to Mutant Huntingtin.Cellular and molecular neurobiology · 2023Article
- Coaggregation of polyglutamine (polyQ) proteins is mediated by polyQ-tract interactions and impairs cellular proteostasis.Acta biochimica et biophysica Sinica · 2023Article
- Implications of specific lysine residues within ataxin-3 for the molecular pathogenesis of Machado-Joseph disease.Frontiers in molecular neuroscience · 2023Article
- Ubiquitin-modifying enzymes in Huntington's disease.Frontiers in molecular biosciences · 2023Review
- Editorial: The role of posttranslational modifications in polyglutamine diseases.Frontiers in molecular neuroscience · 2023Article
- Site-specific ubiquitination: Deconstructing the degradation tag.Current opinion in structural biology · 2022Review
- Hornerin deposits in neuronal intranuclear inclusion disease: direct identification of proteins with compositionally biased regions in inclusions.Acta neuropathologica communications · 2022Article
- A short binding site in the KPC1 ubiquitin ligase mediates processing of NF-κB1 p105 to p50: A potential for a tumor-suppressive PROTAC.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Emerging roles of the HECT-type E3 ubiquitin ligases in hematological malignancies.Discover oncology · 2021Review
- PolyQ-expanded proteins impair cellular proteostasis of ataxin-3 through sequestering the co-chaperone HSJ1 into aggregates.Scientific reports · 2021Article
Corrections and comments
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Authors and funding
10 authors at 4 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Huntington's disease (HD) is a progressive incurable neurodegenerative disorder characterized by motor and neuropsychiatric symptoms. It is caused by expansion of a cytosine-adenine-guanine triplet in the N-terminal domain of exon 1 in the huntingtin (HTT) gene that codes for an expanded polyglutamine stretch in the protein product which becomes aggregation prone. The mutant Htt (mHtt) aggregates are associated with components of the ubiquitin-proteasome system, suggesting that mHtt is marked for proteasomal degradation and that, for reasons still debated, are not properly degraded. We used a novel HD rat model, proteomic analysis, and long-term live neuronal imaging to characterize the effects of ubiquitination on aggregation of mHtt and subsequent cellular responses. We identified two lysine residues, 6 and 9, in the first exon of mHtt that are specifically ubiquitinated in striatal and cortical brain tissues of mHtt-transgenic animals. Expression of mHtt exon 1 lacking these ubiquitination sites in cortical neurons and cultured cells was found to slow aggregate appearance rates and reduce their size but at the same time increase the number of much smaller and less visible ones. Importantly, expression of this form of mHtt was associated with elevated death rates. Proteomic analysis indicated that cellular reactions to mHtt expression were weaker in cells expressing the lysineless protein, possibly implying a reduced capacity to cope with the proteotoxic stress. Taken together, the findings suggest a novel role for ubiquitination-attenuation of the pathogenic effect of mHtt.
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