Pan Yongcheng, Jiang Ying, Wan Juan, Hu Zhengmao, Jiang Hong, Shen Lu, Tang Beisha, Tian Yun, Liu Qiong
Department of Neurology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, 410008, Hunan, China.
Cell Biosci. 2023 Aug 29;13(1):157. doi: 10.1186/s13578-023-01111-6.
Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disorder characterized by widespread intranuclear inclusions in the nervous system as well as multiple visceral organs. In 2019, expanded GGC repeats within the 5' untranslated region of the NOTCH2NLC gene was identified as the causative factor. NIID is a heterogeneous disorder with variable clinical manifestations including cognitive impairment, cerebellar ataxia, parkinsonism, paroxysmal symptoms, autonomic dysfunction, and muscle weakness. Although NIID primarily affects the central and peripheral nervous systems, growing evidence suggests potential cardiac abnormalities in NIID. However, the link between expanded GGC repeats within NOTCH2NLC and cardiac dysfunction remains uncertain.
In this study, we utilized two transgenic mouse models, expressing NOTCH2NLC-(GGC) ubiquitously or specifically in cardiomyocytes, and identified p62 (also known as sequestosome 1, SQSTM1)-positive intranuclear NOTCH2NLC-polyG inclusions in cardiomyocytes in two mouse models. We observed that both models exhibited cardiac-related pathological and echocardiographic changes, albeit exhibiting varying degrees of severity. Transcriptomic analysis revealed shared downregulation of genes related to ion channels and mitochondria in both models, with the cardiomyocyte-specific mice showing a more pronounced downregulation of mitochondria and energy metabolism-related pathways. Further investigations revealed decreased expression of mitochondria-related genes and electron transport chain activity. At last, we conducted a retrospective review of cardiac-related examination results from NIID patients at our hospital and also identified some cardiac abnormalities in NIID patients.
Our study provided the first in vivo evidence linking GGC repeat expansions within NOTCH2NLC to cardiac abnormalities and highlighted the contribution of mitochondrial dysfunction in the development of cardiac abnormalities.
神经元核内包涵体病（NIID）是一种罕见的神经退行性疾病，其特征是神经系统以及多个内脏器官中广泛存在核内包涵体。2019年，NOTCH2NLC基因5'非翻译区内扩展的GGC重复序列被确定为致病因素。NIID是一种临床表现多样的异质性疾病，包括认知障碍、小脑共济失调、帕金森综合征、发作性症状、自主神经功能障碍和肌肉无力。虽然NIID主要影响中枢和周围神经系统，但越来越多的证据表明NIID存在潜在的心脏异常。然而，NOTCH2NLC内扩展的GGC重复序列与心脏功能障碍之间的联系仍不确定。
在本研究中，我们利用了两种转基因小鼠模型，一种在全身普遍表达NOTCH2NLC-(GGC)，另一种在心肌细胞中特异性表达，在两种小鼠模型的心肌细胞中均鉴定出p62（也称为聚集体自噬受体1，SQSTM1）阳性的核内NOTCH2NLC-多聚G包涵体。我们观察到两种模型均出现了与心脏相关的病理和超声心动图变化，尽管严重程度不同。转录组分析显示，两种模型中与离子通道和线粒体相关的基因均下调，心肌细胞特异性小鼠中线粒体和能量代谢相关途径的下调更为明显。进一步研究发现线粒体相关基因的表达和电子传递链活性降低。最后，我们回顾性分析了我院NIID患者的心脏相关检查结果，也发现了NIID患者存在一些心脏异常。
我们的研究首次提供了体内证据，证明NOTCH2NLC内的GGC重复序列扩展与心脏异常有关，并强调了线粒体功能障碍在心脏异常发生中的作用。
