VPS35 dysfunction impairs lysosomal degradation of alpha-synuclein and exacerbates neurotoxicity in a Drosophila model of Parkinson's disease

摘要

Mutations in vacuolar protein sorting 35 (VPS35) have been linked to familial Parkinson's disease (PD). VPS35, a component of the retromer, mediates the retrograde transport of cargo from the endosome to the trans-Golgi network. Here we showed that retromer depletion increases the lysosomal turnover of the mannose 6-phosphate receptor, thereby affecting the trafficking of cathepsin D (CTSD), a lysosome protease involved in a-synuclein (alpha SYN) degradation. VPS35 knockdown perturbed the maturation step of CTSD in parallel with the accumulation of alpha SYN in the lysosomes. Furthermore, we found that the knockdown of Drosophila VPS35 not only induced the accumulation of the detergent-insoluble alpha SYN species in the brain but also exacerbated both locomotor impairments and mild compound eye disorganization and interommatidial bristle loss in flies expressing human alpha SYN. These findings indicate that the retromer may play a crucial role in alpha SYN degradation by modulating the maturation of CTSD and might thereby contribute to the pathogenesis of the disease. (C) 2014 Elsevier Inc. All rights reserved.