ArticleCell & bioscience2022
Siah-1-interacting protein regulates mutated huntingtin protein aggregation in Huntington's disease models.
Article in Cell & bioscience, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 11 citations in OpenAlex.
- Review
- Ameliorating calcium homeostasis improves longevity and healthspan in progeroid and naturally aged mice.Nature communications · 2026Article
- Long noncoding RNAs in ubiquitination, protein degradation, and human diseases.Biochimica et biophysica acta. Gene regulatory mechanisms · 2024Review
- Excessive STAU1 condensate drives mTOR translation and autophagy dysfunction in neurodegeneration.The Journal of cell biology · 2024Article
- Construction of human 3D striato-nigral assembloids to recapitulate medium spiny neuronal projection defects in Huntington's disease.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Abnormal protein post-translational modifications induces aggregation and abnormal deposition of protein, mediating neurodegenerative diseases.Cell & bioscience · 2024Review
- Mutant-Huntingtin Molecular Pathways Elucidate New Targets for Drug Repurposing.International journal of molecular sciences · 2023Review
- Huntingtin Interacting Proteins and Pathological Implications.International journal of molecular sciences · 2023Review
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
Abstract
backgroundHuntington's disease (HD) is a neurodegenerative disorder whereby mutated huntingtin protein (mHTT) aggregates when polyglutamine repeats in the N-terminal of mHTT exceeds 36 glutamines (Q). However, the mechanism of this pathology is unknown. Siah1-interacting protein (SIP) acts as an adaptor protein in the ubiquitination complex and mediates degradation of other proteins. We hypothesized that mHTT aggregation depends on the dysregulation of SIP activity in this pathway in HD.
resultsA higher SIP dimer/monomer ratio was observed in the striatum in young YAC128 mice, which overexpress mHTT. We found that SIP interacted with HTT. In a cellular HD model, we found that wildtype SIP increased mHTT ubiquitination, attenuated mHTT protein levels, and decreased HTT aggregation. We predicted mutations that should stabilize SIP dimerization and found that SIP mutant-overexpressing cells formed more stable dimers and had lower activity in facilitating mHTT ubiquitination and preventing exon 1 mHTT aggregation compared with wildtype SIP.
conclusionsOur data suggest that an increase in SIP dimerization in HD medium spiny neurons leads to a decrease in SIP function in the degradation of mHTT through a ubiquitin-proteasome pathway and consequently an increase in mHTT aggregation. Therefore, SIP could be considered a potential target for anti-HD therapy during the early stage of HD pathology.
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