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

Neuronal intranuclear inclusion disease (NIID) is a rare, autosomal dominant neurodegenerative disorder characterized by widespread intranuclear inclusions in the nervous system and multiple visceral organs, accompanied by significant clinical heterogeneity. After the identification of GGC repeat expansions in the NOTCH2NLC gene as the causative factor for NIID, a series of models, including AAV-mediated and transgenic animal models, as well as patient-derived cellular models such as brain organoids have been developed to investigate the disease pathogenesis and explore potential therapeutic interventions. These models recapitulate key pathological and behavioral features of NIID, and have uncovered diverse mechanisms. This review summarizes and compares existing NIID animal models and human-derived cell models, explores the advancements in understanding disease pathogenesis achieved through these models, and discusses their limitations. By providing a comprehensive overview, this review aims to guide future model development, deepen the understanding of NIID mechanisms, and facilitate the identification of therapeutic targets for NIID.