Expression of expanded GGC repeats within NOTCH2NLC causes behavioral deficits and neurodegeneration in a mouse model of neuronal intranuclear inclusion disease.

ABSTRACT: GGC repeat expansions within NOTCH2NLC have been identified as the genetic cause of neuronal intranuclear inclusion disease (NIID). To understand the molecular pathogenesis of NIID, here, we established both a transgenic mouse model and a human neural progenitor cells (hNPCs) model. Expression of the NOTCH2NLC with expanded GGC repeats produced widespread intranuclear and perinuclear polyglycine (polyG), polyalanine (polyA), and polyarginine (polyR) inclusions, leading to behavioral deficits and severe neurodegeneration, which faithfully mimicked the clinical and pathological features associated with NIID. Furthermore, conserved alternative splicing events were identified between the NIID mouse and hNPC models, among which was the enrichment of the binding motifs of hnRNPM, a

SUBMITTER: Liu Q 

PROVIDER: S-EPMC9683706 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature