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Insights into RNA-mediated pathology in new mouse models of Huntington's disease

dc.abstract.enHuntington's disease (HD) is a neurodegenerative polyglutamine (polyQ) disease resulting from the expansion of CAG repeats located in the ORF of the huntingtin gene (HTT). The extent to which mutant mRNA-driven disruptions contribute to HD pathogenesis, particularly in comparison to the dominant mechanisms related to the gain-of-function effects of the mutant polyQ protein, is still debatable. To evaluate this contribution in vivo, we generated two mouse models through a knock-in strategy at the Rosa26 locus. These models expressed distinct variants of human mutant HTT cDNA fragment: a translated variant (HD/100Q model, serving as a reference) and a nontranslated variant (HD/100CAG model). The cohorts of animals were subjected to a broad spectrum of molecular, behavioral, and cognitive analysis for 21 months. Behavioral testing revealed alterations in both models, with the HD/100Q model exhibiting late disease phenotype. The rotarod, static rod, and open-field tests showed some motor deficits in HD/100CAG and HD/100Q model mice during the light phase, while ActiMot indicated hyperkinesis during the dark phase. Both models also exhibited certain gene deregulations in the striatum that are related to disrupted pathways and phenotype alterations observed in HD. In conclusion, we provide in vivo evidence for a minor contributory role of mutant RNA in HD pathogenesis. The separated effects resulting from the presence of mutant RNA in the HD/100CAG model led to less severe but, to some extent, similar types of impairments as in the HD/100Q model. Increased anxiety was one of the most substantial effects caused by mutant HTT RNA.
dc.affiliationWydział Rolnictwa, Ogrodnictwa i Bioinżynierii
dc.affiliation.instituteKatedra Biochemii i Biotechnologii
dc.contributor.authorWozna‐Wysocka, Magdalena
dc.contributor.authorJazurek‐Ciesiolka, Magdalena
dc.contributor.authorPrzybyl, Lukasz
dc.contributor.authorWronka, Dorota
dc.contributor.authorMisiorek, Julia Oliwia
dc.contributor.authorSuszyńska-Zajczyk, Joanna
dc.contributor.authorFigura, Grzegorz
dc.contributor.authorCiesiolka, Adam
dc.contributor.authorSobieszczanska, Paula
dc.contributor.authorZeller, Anna
dc.contributor.authorNiemira, Magdalena
dc.contributor.authorSwitonski, Pawel Michal
dc.contributor.authorFiszer, Agnieszka
dc.date.access2025-08-05
dc.date.accessioned2025-08-05T10:12:47Z
dc.date.available2025-08-05T10:12:47Z
dc.date.copyright2024-11-27
dc.date.issued2024
dc.description.abstract<jats:title>Abstract</jats:title><jats:p>Huntington's disease (HD) is a neurodegenerative polyglutamine (polyQ) disease resulting from the expansion of CAG repeats located in the ORF of the huntingtin gene (<jats:italic>HTT</jats:italic>). The extent to which mutant mRNA‐driven disruptions contribute to HD pathogenesis, particularly in comparison to the dominant mechanisms related to the gain‐of‐function effects of the mutant polyQ protein, is still debatable. To evaluate this contribution in vivo, we generated two mouse models through a knock‐in strategy at the <jats:italic>Rosa26</jats:italic> locus. These models expressed distinct variants of human mutant <jats:italic>HTT</jats:italic> cDNA fragment: a translated variant (HD/100Q model, serving as a reference) and a nontranslated variant (HD/100CAG model). The cohorts of animals were subjected to a broad spectrum of molecular, behavioral, and cognitive analysis for 21 months. Behavioral testing revealed alterations in both models, with the HD/100Q model exhibiting late disease phenotype. The rotarod, static rod, and open‐field tests showed some motor deficits in HD/100CAG and HD/100Q model mice during the light phase, while ActiMot indicated hyperkinesis during the dark phase. Both models also exhibited certain gene deregulations in the striatum that are related to disrupted pathways and phenotype alterations observed in HD. In conclusion, we provide in vivo evidence for a minor contributory role of mutant RNA in HD pathogenesis. The separated effects resulting from the presence of mutant RNA in the HD/100CAG model led to less severe but, to some extent, similar types of impairments as in the HD/100Q model. Increased anxiety was one of the most substantial effects caused by mutant <jats:italic>HTT</jats:italic> RNA.</jats:p>
dc.description.accesstimeat_publication
dc.description.bibliographyil., bibliogr.
dc.description.financepublication_nocost
dc.description.financecost0,00
dc.description.if4,2
dc.description.number23
dc.description.points140
dc.description.versionfinal_published
dc.description.volume38
dc.identifier.doi10.1096/fj.202401465R
dc.identifier.eissn1530-6860
dc.identifier.issn0892-6638
dc.identifier.urihttps://sciencerep.up.poznan.pl/handle/item/4078
dc.identifier.weblinkhttps://faseb.onlinelibrary.wiley.com/doi/10.1096/fj.202401465R
dc.languageen
dc.relation.ispartofFASEB Journal
dc.relation.pagese70182
dc.rightsCC-BY
dc.sciencecloudnosend
dc.share.typeOTHER
dc.subject.enHuntington's disease
dc.subject.enmouse model
dc.subject.enneurodegenerative diseases
dc.subject.enpolyglutamine disorders
dc.subject.enRNA toxicity
dc.titleInsights into RNA-mediated pathology in new mouse models of Huntington's disease
dc.typeJournalArticle
dspace.entity.typePublication
oaire.citation.issue23
oaire.citation.volume38