دورية أكاديمية
Neuron type‐specific increase in lamin B1 contributes to nuclear dysfunction in Huntington’s disease
العنوان: | Neuron type‐specific increase in lamin B1 contributes to nuclear dysfunction in Huntington’s disease |
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المؤلفون: | Rafael Alcalá‐Vida, Marta Garcia‐Forn, Carla Castany‐Pladevall, Jordi Creus‐Muncunill, Yoko Ito, Enrique Blanco, Arantxa Golbano, Kilian Crespí‐Vázquez, Aled Parry, Guy Slater, Shamith Samarajiwa, Sandra Peiró, Luciano Di Croce, Masashi Narita, Esther Pérez‐Navarro |
المصدر: | EMBO Molecular Medicine, Vol 13, Iss 2, Pp n/a-n/a (2021) |
بيانات النشر: | Springer Nature, 2021. |
سنة النشر: | 2021 |
المجموعة: | LCC:Medicine (General) LCC:Genetics |
مصطلحات موضوعية: | chromatin accessibility, LAD, nuclear morphology, nuclear permeability, R6/1 mouse, Medicine (General), R5-920, Genetics, QH426-470 |
الوصف: | 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. |
نوع الوثيقة: | article |
وصف الملف: | electronic resource |
اللغة: | English |
تدمد: | 1757-4684 1757-4676 |
Relation: | https://doaj.org/toc/1757-4676; https://doaj.org/toc/1757-4684 |
DOI: | 10.15252/emmm.202012105 |
URL الوصول: | https://doaj.org/article/127bba476357472aa2d34c9d8e7f0916 |
رقم الأكسشن: | edsdoj.127bba476357472aa2d34c9d8e7f0916 |
قاعدة البيانات: | Directory of Open Access Journals |
تدمد: | 17574684 17574676 |
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DOI: | 10.15252/emmm.202012105 |