Neuron Type-specific Increase in Lamin B1 Contributes to Nuclear Dysfunction in Huntington's Disease

Overview

Journal EMBO Mol Med

Specialty Molecular Biology

Date 2020 Dec 28

PMID 33369245

Citations 23

Authors

Rafael Alcala-Vida

Marta Garcia-Forn

Carla Castany-Pladevall

Jordi Creus-Muncunill

Yoko Ito

Enrique Blanco

Arantxa Golbano

Kilian Crespi-Vazquez

Aled Parry

Guy Slater

Shamith Samarajiwa

Sandra Peiro

Luciano Di Croce

Masashi Narita

Esther Perez-Navarro

Affiliations

Soon will be listed here.

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.

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