Expression of expanded GGC repeats within NOTCH2NLC causes cardiac dysfunction in mouse models

Cell & Bioscience

Research

Ying Jiang¹  Zhengmao Hu¹  Yun Tian²  Juan Wan³  Yongcheng Pan⁴  Qiong Liu⁴  Beisha Tang⁵  Hong Jiang⁶  Lu Shen⁶ 

[1] Centre for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, 410078, Changsha, Hunan, China;Department of Geriatrics, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China;Department of Neurology, Multi-Omics Research Center for Brain Disorders, The First Affiliated Hospital, Hengyang Medical School, University of South China, 421000, Hengyang, Hunan, China;Department of Neurology, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China;Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, 410008, Changsha, Hunan, China;Department of Neurology, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China;Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, 410008, Changsha, Hunan, China;Department of Neurology, Multi-Omics Research Center for Brain Disorders, The First Affiliated Hospital, Hengyang Medical School, University of South China, 421000, Hengyang, Hunan, China;National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China;Department of Neurology, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China;Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, 410008, Changsha, Hunan, China;National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China;

关键词: NOTCH2NLC;    GGC repeat expansion;    NOTCH2NLC-polyG inclusions;    Cardiomyocyte;    Cardiac dysfunction;    Mitochondria;   

DOI  :  10.1186/s13578-023-01111-6

 received in 2023-08-01, accepted in 2023-08-23,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundNeuronal 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.ResultsIn this study, we utilized two transgenic mouse models, expressing NOTCH2NLC-(GGC)98 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.ConclusionsOur 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.

【 授权许可】

CC BY   
© Society of Chinese Bioscientists in America (SCBA) 2023

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