Sequestration of cellular interacting partners by protein aggregates: implication in a loss-of-function pathology

Protein misfolding and aggregation are a hallmark of several neurodegenerative diseases (NDs). However, how protein aggregation leads to cytotoxicity and neurodegeneration is still controversial. Emerging evidence demonstrates that sequestration of cellular-interacting partners by protein aggregates contributes to the pathogenesis of these diseases. Here, we review current research on sequestration of cellular proteins by protein aggregates and its relation to proteinopathies. Based on different interaction modes, we classify these protein sequestrations into four types: protein coaggregation, domain/motif-mediated sequestration, RNA-assisted sequestration, and sequestration of molecular chaperones. Thus, the cellular essential proteins and/or RNA hijacked by protein aggregates may lose their biological functions, consequently resulting in cytotoxicity and neurodegeneration. We have proposed a hijacking model recapitulating the sequestration process and the loss-of-function pathology of ND.