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

Area of Science:

• Neurogenetics
• Cardiovascular Research
• Mitochondrial Biology

Background:

• Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disorder caused by GGC repeat expansions in the NOTCH2NLC gene.
• NIID presents with diverse neurological symptoms, and cardiac involvement is increasingly suspected but not fully understood.
• The precise mechanism linking NOTCH2NLC gene mutations to cardiac dysfunction remains unclear.

Purpose of the Study:

• To investigate the direct link between NOTCH2NLC GGC repeat expansions and cardiac abnormalities in vivo.
• To elucidate the role of mitochondrial dysfunction in the pathogenesis of NIID-associated cardiac issues.
• To explore potential cardiac manifestations in human patients with NIID.

Main Methods:

• Utilized two transgenic mouse models expressing NOTCH2NLC-(GGC)98, one with ubiquitous expression and another with cardiomyocyte-specific expression.
• Performed pathological and echocardiographic assessments to evaluate cardiac function and structure in the mouse models.
• Conducted transcriptomic analysis to identify molecular pathways affected in the heart, focusing on gene expression related to mitochondria and ion channels.
• Analyzed mitochondrial gene expression and electron transport chain activity.
• Retrospectively reviewed cardiac examination data from NIID patients.

Main Results:

• Both mouse models developed intranuclear NOTCH2NLC-polyG inclusions in cardiomyocytes and exhibited cardiac pathological and echocardiographic changes.
• Transcriptomic analysis revealed significant downregulation of genes involved in mitochondrial function and energy metabolism in both models, more pronounced in cardiomyocyte-specific models.
• Decreased expression of mitochondria-related genes and reduced electron transport chain activity were observed.
• Retrospective analysis of NIID patients identified cardiac abnormalities, supporting the in vivo findings.

Conclusions:

• This study provides the first in vivo evidence directly linking NOTCH2NLC GGC repeat expansions to cardiac abnormalities.
• Mitochondrial dysfunction is identified as a key contributor to the development of cardiac abnormalities in the context of NIID.
• The findings suggest that cardiac assessment should be considered in the management of NIID patients.