Neuron-specific increase in lamin B1 disrupts nuclear function in Huntington's disease
Alcala-Vida, R.; Garcia-Forn, M.; Creus-Muncunill, J.; Ito, Y.; Blanco, E.; Castany-Pladevall, C.; Crespi-Vazquez, K.; Parry, A.; Slater, G.; Samarajiwa, S.; Peiro, S.; Di Croce, L.; Narita, M.; Perez-Navarro, E.
Show abstract
Lamins are crucial proteins for nuclear functionality. Here, we provide new evidence showing an involvement of increased lamin B1 levels in the pathophysiology of Huntingtons disease (HD), a CAG repeat-associated neurodegenerative disorder. Through fluorescence-activated nuclear suspension imaging we demonstrate 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, which could contribute to transcriptional alterations we determined by RNA sequencing. Supporting lamin B1 alterations as a causal role in mutant-huntingtin mediated neurodegeneration, pharmacological normalization of lamin B1 levels by betulinic acid administration in the R6/1 mouse model of HD restored nuclear homeostasis and prevented motor and cognitive dysfunction. Collectively, our work point out increased lamin B1 levels as a new pathogenic mechanism in HD and provides a novel target for its intervention.
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