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Title: Neuron type-specific increase in lamin B1 contributes to nuclear dysfunction in Huntington's disease
Author: 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
Keywords: Corea de Huntington
Models animals en la investigació
Huntington's chorea
Animal models in research
Issue Date: 5-Feb-2021
Publisher: EMBO Press
Abstract: 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.
Note: Reproducció del document publicat a:
It is part of: EMBO Molecular Medicine, 2021, vol. 13, num. 2, p. e12105
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ISSN: 1757-4676
Appears in Collections:Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)
Articles publicats en revistes (Biomedicina)

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