GGC repeat expansion in NOTCH2NLC induces dysfunction in ribosome biogenesis and translation.

This article focuses on the pathogenic mechanisms of GGC repeat expansion in the 5′ untranslated region of the human-specific gene NOTCH2NLC, which is associated with neuronal intranuclear inclusion disease (NIID) and other neurological disorders. Using patient-derived induced pluripotent stem cell (iPSC) models, including 3D cerebral organoids (3DCOs) and neurons, the study demonstrates that NOTCH2NLC GGC repeats induce the formation of toxic polyglycine-containing intranuclear inclusions, enhance autophagic flux, activate the integrated stress response via EIF2α phosphorylation, and impair ribosome biogenesis and translation. Single-cell and bulk RNA sequencing revealed downregulation of ribosomal protein genes and altered neural cell composition, suggesting disrupted brain development. Additionally, the repeats cause nucleolar stress, promote stress granule formation, and inhibit global protein synthesis, providing insights into the molecular pathology underlying NIID.