| First Author | Alcalá-Vida R | Year | 2021 |
| Journal | EMBO Mol Med | Volume | 13 |
| Issue | 2 | Pages | e12105 |
| PubMed ID | 33369245 | Mgi Jnum | J:314611 |
| Mgi Id | MGI:6804630 | Doi | 10.15252/emmm.202012105 |
| Citation | Alcala-Vida R, et al. (2021) Neuron type-specific increase in lamin B1 contributes to nuclear dysfunction in Huntington's disease. EMBO Mol Med 13(2):e12105 |
| abstractText | 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. |
