Artykuł w czasopiśmie
Brak miniatury
Licencja
ClosedAccessDostęp zamknięty
 

Siah-1-interacting protein regulates mutated huntingtin protein aggregation in Huntington’s disease models

Uproszczony widok
cris.lastimport.scopus2024-02-12T20:19:38Z
dc.abstract.enackground: Huntington'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. Results: A 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. Conclusions: Our 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.
dc.affiliationUniwersytet Warszawski
dc.contributor.authorDunin-Horkawicz, Stanisław
dc.contributor.authorKuźnicki, Jacek
dc.contributor.authorKorzeniowska, Małgorzata
dc.contributor.authorCZEREDYS, MAGDALENA
dc.contributor.authorLudwiczak, Jan
dc.contributor.authorLatoszek, Ewelina
dc.date.accessioned2024-01-26T07:36:16Z
dc.date.available2024-01-26T07:36:16Z
dc.date.issued2022
dc.description.financeNie dotyczy
dc.description.number1
dc.description.volume12
dc.identifier.doi10.1186/S13578-022-00755-0
dc.identifier.issn2045-3701
dc.identifier.urihttps://repozytorium.uw.edu.pl//handle/item/119776
dc.identifier.weblinkhttps://link.springer.com/content/pdf/10.1186/s13578-022-00755-0.pdf
dc.languageeng
dc.pbn.affiliationbiological sciences
dc.relation.ispartofCell and Bioscience
dc.relation.pages34
dc.rightsClosedAccess
dc.sciencecloudnosend
dc.subject.enAggregation
dc.subject.enHuntingtin
dc.subject.enHuntington’s disease
dc.subject.enSiah-1-interacting protein
dc.subject.enUbiquitination
dc.titleSiah-1-interacting protein regulates mutated huntingtin protein aggregation in Huntington’s disease models
dc.typeJournalArticle
dspace.entity.typePublication