RNF216 dysfunction: unraveling its nuclear role in biomolecular condensates and splicing regulation

Dementia is a growing global crisis with no curative treatments. This proposal investigates the role of the E3 ubiquitin ligase RNF216 in neurodegeneration, as mutations in this gene are linked to an ultra-rare disorder characterized by early-onset dementia, ataxia, and choreatic movements. Neuropathological studies suggest that RNF216 dysfunction disrupts protein homeostasis, contributing to neurodegeneration. We hypothesize that RNF216 localizes to the nucleus, where it regulates biomolecular condensate formation and splicing. Its dysfunction may impair splicing, promote intranuclear inclusions, and drive neurodegeneration. To explore this, we will comprehensively profile RNF216 expression in the human brain and confirm its nuclear localization in brain tissue. Furthermore, we will investigate its role in nuclear biomolecular condensate dynamics and splicing regulation. To establish a causal link between RNF216 dysfunction, splicing defects, intranuclear protein aggregation, and neurodegeneration, we will develop hiPSC models. This research aims to uncover fundamental disease mechanisms, bridging the gap between rare and common neurodegenerative disorders.

Keywords:splicing, biomolecular condensates, RNF216-mediated neurodegeneration

Disciplines:Transcriptomics, Neurological and neuromuscular diseases, Genetics, Cell, tissue and organ engineering, Cell physiology