Alcalá Vida, RafaelGarcia-Forn, MartaCastany Pladevall, CarlaCreus Muncunill, JordiIto, YokoBlanco, EnriqueGolbano, ArantxaCrespí-Vázquez, KilianParry, AledSlater, GuySamarajiwa, ShamithPeiró, SandraCroce, Luciano DiNarita, MasashiPérez Navarro, Esther2021-03-152021-03-152021-02-051757-4676https://hdl.handle.net/2445/175086Lamins are crucial proteins for nuclear functionality. Here, we provide new evidence showing that increased lamin B1 levels contribute to the pathophysiology of Huntington's disease (HD), a CAG repeat-associated neurodegenerative disorder. Through fluorescence-activated nuclear suspension imaging, we show that nucleus from striatal medium-sized spiny and CA1 hippocampal neurons display increased lamin B1 levels, in correlation with altered nuclear morphology and nucleocytoplasmic transport disruption. Moreover, ChIP-sequencing analysis shows an alteration of lamin-associated chromatin domains in hippocampal nuclei, accompanied by changes in chromatin accessibility and transcriptional dysregulation. Supporting lamin B1 alterations as a causal role in mutant huntingtin-mediated neurodegeneration, pharmacological normalization of lamin B1 levels in the hippocampus of the R6/1 mouse model of HD by betulinic acid administration restored nuclear homeostasis and prevented motor and cognitive dysfunction. Collectively, our work points increased lamin B1 levels as a new pathogenic mechanism in HD and provides a novel target for its intervention.25 p.application/pdfengcc-by (c) Alcalá Vida, Rafael et al., 2021http://creativecommons.org/licenses/by/3.0/esCorea de HuntingtonModels animals en la investigacióHuntington's choreaAnimal models in researchinfo:eu-repo/semantics/article7085372021-03-15info:eu-repo/semantics/openAccess33369245