Parkin-mediated ubiquitin signalling in aggresome formation and autophagy

Abstract

Understanding how cells handle and dispose of misfolded proteins is of paramount importance because protein misfolding and aggregation underlie the pathogenesis of many neurodegenerative disorders, including PD (Parkinson's disease) and Alzheimer's disease. In addition to the ubiquitin–proteasome system, the aggresome–autophagy pathway has emerged as another crucial cellular defence system against toxic build-up of misfolded proteins. In contrast with basal autophagy that mediates non-selective, bulk clearance of misfolded proteins along with normal cellular proteins and organelles, the aggresome–autophagy pathway is increasingly recognized as a specialized type of induced autophagy that mediates selective clearance of misfolded and aggregated proteins under the conditions of proteotoxic stress. Recent evidence implicates PD-linked E3 ligase parkin as a key regulator of the aggresome–autophagy pathway and indicates a signalling role for Lys63-linked polyubiquitination in the regulation of aggresome formation and autophagy. The present review summarizes the current knowledge of the aggresome–autophagy pathway, its regulation by parkin-mediated Lys63-linked polyubiquitination, and its dysfunction in neurodegenerative diseases.