Huntington’s disease as a lamin B1 nuclear envelopathy. Huntington’s disease as a lamin B1 nuclear envelopathy

Lamins, the major structural proteins within the nuclear lamina, are crucial for the functionality of cellular nucleus and their alterations are involved in the so-called laminopathies. We previously found that Huntington’s disease (HD), a hereditary neurodegenerative disorder caused by an expansion of a CAG repeat in the huntingtin (htt) gene, courses with increased lamin B protein levels in specific brain regions in both mouse models and patients. We now show that these changes are mostly restricted to lamin B1, occur in striatal medium-sized spiny neurons and CA1 hippocampal neurons, and are accompanied by altered nuclear morphology, nucleocytoplasmic transport disruption and un-structuring of lamin-associated chromatin domains. Normalization of lamin B1 levels by betulinic acid administration in the R6/1 mouse model of HD results in beneficial restoring of nuclear lamina homeostasis and prevention of motor and cognitive dysfunction, opening a window for a new therapeutic approach for HD and other B1-type laminophaties. Overall design: ChIP-seq (36 samples), RNA-seq (18 samples) and ATAC-seq (6 samples) of 30-week-old WT and R6/1 mice hippocampus. WT means Wild-type mice and R6/1 means R6/1 Huntington's disease transgenic mice (PubMed ID 8898202)

核纤层蛋白（lamins）是核纤层（nuclear lamina）内的主要结构蛋白，对细胞核功能至关重要，其异常改变与所谓的核纤层蛋白病（laminopathies）密切相关。我们此前发现，亨廷顿舞蹈症（Huntington’s disease, HD）——一种由亨廷顿（huntingtin, htt）基因CAG重复扩增所导致的遗传性神经退行性疾病——在小鼠模型与患者的特定脑区中，病程均伴随核纤层蛋白B（lamin B）水平升高的特征。本研究证实，此类变化主要局限于核纤层蛋白B1（lamin B1），且出现在纹状体中型多棘神经元与海马CA1区神经元中，同时伴随核形态异常、核质运输紊乱以及核纤层相关染色质结构域的去结构化。在亨廷顿舞蹈症R6/1小鼠模型中，通过白桦脂酸（betulinic acid）干预使核纤层蛋白B1水平恢复正常，可有效恢复核纤层稳态，并改善运动与认知功能障碍，为亨廷顿舞蹈症及其他B1型核纤层蛋白病开辟了全新的治疗途径。实验设计概况：对30周龄野生型（Wild-type, WT）与R6/1亨廷顿舞蹈症转基因小鼠（PubMed ID: 8898202）的海马组织开展染色质免疫共沉淀测序（ChIP-seq，共36例样本）、RNA测序（RNA-seq，共18例样本）以及转座酶可及性测序（ATAC-seq，共6例样本），其中WT指代野生型小鼠，R6/1指代R6/1亨廷顿舞蹈症转基因小鼠。