Increased expression of p62/SQSTM1 in prion diseases and its association with pathogenic prion protein

Abstract

Prion diseases are neurodegenerative disorders characterized by the aggregation of abnormally folded prion protein (PrP Sc). In this study, we focused on the mechanism of clearance of PrP Sc, which remains unclear. p62 is a cytosolic protein known to mediate both the formation and degradation of aggregates of abnormal proteins. The levels of p62 protein increased in prion-infected brains and persistently infected cell cultures. Upon proteasome inhibition, p62 co-localized with PrP Sc, forming a large aggregate in the perinuclear region, hereafter referred to as PrP Sc -aggresome. These aggregates were surrounded with autophagosome marker LC3 and lysosomes in prion-infected cells. Moreover, transient expression of the phosphomimic form of p62, which has enhanced ubiquitin-binding activity, reduced the amount of PrP Sc in prion-infected cells, indicating that the activation of p62 could accelerate the clearance of PrP Sc. Our findings would thus suggest that p62 could be a target for the therapeutic control of prion diseases.