Modeling neuronal intranuclear inclusion disease: A review of animal and human-derived cellular models and mechanistic insights

Neuronal intranuclear inclusion disease (NIID) is a rare autosomal dominant neurodegenerative disorder defined by the presence of eosinophilic intranuclear inclusions across both central and peripheral components of the nervous system, as well as multiple visceral organs, resulting in pronounced clinical heterogeneity. Following the discovery of pathogenic GGC repeat expansions in the NOTCH2NLC gene as the underlying genetic driver, a diverse array of experimental platforms has been established to probe NIID pathogenesis, including adeno-associated virus-mediated expression systems, transgenic animal models, and patient-derived cellular systems such as brain organoids. Collectively, these models recapitulate key histopathological and behavioral phenotypes observed in NIID and have elucidated multiple molecular and cellular pathways implicated in disease progression. This review systematically examines the current landscape of NIID model systems, highlighting their respective contributions to understanding disease pathogenesis, evaluating their experimental limitations, and identifying avenues for future refinement. Such integrative analysis is critical for advancing the development of more faithful disease models and facilitating the identification of therapeutic targets for NIID.