Neuron type-specific increase in lamin B1 contributes to nuclear dysfunction in Huntington's disease.

Rafael Alcalá‐Vida,Shamith Samarajiwa,Sandra Peiró,Aled Parry,Kilian Crespí‐Vázquez,Arantxa Golbano,Yoko Ito,Enrique Blanco,Marta Garcia‐Forn,Jordi Creus‐Muncunill,Carla Castany‐Pladevall,Luciano Di Croce,Guy Slater,Esther Pérez‐Navarro,Masashi Narita

doi:10.15252/emmm.202012105

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.

Highlights

Lamins are type V intermediate filaments that together with laminbinding proteins are embedded into the inner nuclear membrane and constitute the nuclear lamina
We show that (I) lamin B1 protein levels are increased in vulnerable regions of Huntington’s disease (HD) brain correlating with altered nuclear morphology; (II) nucleocytoplasmic transport of small molecules is altered in neurons showing increased lamin B1 levels in R6/1 mouse brain; (III) in R6/1 mice hippocampus (a) lamin B1 alterations correlate with partial unstructuring of lamin-associated domains (LADs) and (b) changes in chromatin accessibility mostly localize at distal regulatory elements, correlate with transcriptional dysregulation, and are partially associated with lamin B1 chromatin-binding alterations; and (IV) pharmacologic regulation of lamin B1 levels improves nucleocytoplasmic transport in Cornu ammonis 1 (CA1) hippocampal neurons and ameliorates behavioral abnormalities in R6/1 mouse
Among all lamin isoforms, lamin B1 was consistently affected in the brain of both HD patients and mouse models from early stages of the disease

Summary

Introduction

Lamins are type V intermediate filaments that together with laminbinding proteins are embedded into the inner nuclear membrane and constitute the nuclear lamina (de Leeuw et al, 2018). This family of proteins is classified into two subgroups: A-type lamins (lamins A and C), encoded by the LMNA gene, and B-type lamins (lamins B1 and B2), encoded by LMNB1 and LMNB2 genes, respectively (de Leeuw et al, 2018). While lamins A and C are expressed exclusively in differentiated cells, lamin B is present in almost all cell types independently of their differentiation state (Verstraeten et al, 2007).

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