Expression of expanded GGC repeats within NOTCH2NLC causes cardiac dysfunction in mouse models
Background: 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. 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. Results: In this study, we utilized two transgenic mouse models, expressing NOTCH2NLC-(GGC)98 ubiquitously or specifically in cardiomyocytes, and identified p62-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.  Conclusions: 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. Overall design: To explore the underlying mechanisms leading to cardiac dysfunction upon the expression of NOTCH2NLC-(GGC)98 in cardiomyocytes, we performed RNA-seq analysis on heart tissues from the E2a-tg (ubiquitously expressed) mice at P30 (postnatal 30 days) and Myh6-tg (specifically expressed in cardiomyocytes after tamoxifen injection) mice at P90 (postnatal 90 days, 30 days after the first tamoxifen injection), along with age-matched control mice.