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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/175086
Neuron type-specific increase in lamin B1 contributes to nuclear dysfunction in Huntington's disease
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Lamins 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.
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ALCALÁ VIDA, Rafael, GARCIA-FORN, Marta, CASTANY PLADEVALL, Carla, CREUS MUNCUNILL, Jordi, ITO, Yoko, BLANCO, Enrique, GOLBANO, Arantxa, CRESPÍ-VÁZQUEZ, Kilian, PARRY, Aled, SLATER, Guy, SAMARAJIWA, Shamith, PEIRÓ, Sandra, CROCE, Luciano di, NARITA, Masashi, PÉREZ NAVARRO, Esther. Neuron type-specific increase in lamin B1 contributes to nuclear dysfunction in Huntington's disease. _EMBO Molecular Medicine_. 2021. Vol. 13, núm. 2, pàgs. e12105. [consulta: 25 de gener de 2026]. ISSN: 1757-4676. [Disponible a: https://hdl.handle.net/2445/175086]