RRC ID 31693
Author Miura E, Hasegawa T, Konno M, Suzuki M, Sugeno N, Fujikake N, Geisler S, Tabuchi M, Oshima R, Kikuchi A, Baba T, Wada K, Nagai Y, Takeda A, Aoki M.
Title VPS35 dysfunction impairs lysosomal degradation of α-synuclein and exacerbates neurotoxicity in a Drosophila model of Parkinson's disease.
Journal Neurobiol Dis
Abstract 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 α-synuclein (αSYN) degradation. VPS35 knockdown perturbed the maturation step of CTSD in parallel with the accumulation of αSYN in the lysosomes. Furthermore, we found that the knockdown of Drosophila VPS35 not only induced the accumulation of the detergent-insoluble αSYN species in the brain but also exacerbated both locomotor impairments and mild compound eye disorganization and interommatidial bristle loss in flies expressing human αSYN. These findings indicate that the retromer may play a crucial role in αSYN degradation by modulating the maturation of CTSD and might thereby contribute to the pathogenesis of the disease.
Volume 71
Pages 1-13
Published 2014-11-1
DOI 10.1016/j.nbd.2014.07.014
PII S0969-9961(14)00215-0
PMID 25107340
MeSH Animals Animals, Genetically Modified Brain / metabolism Brain / pathology Cathepsin D / metabolism Disease Models, Animal Drosophila Drosophila Proteins / genetics* Eye / metabolism Eye / pathology Gene Expression Regulation / genetics HEK293 Cells Humans Immunoprecipitation Locomotion / genetics Lysosomes / metabolism* Mutation / genetics* Parkinson Disease / genetics* Parkinson Disease / metabolism* Parkinson Disease / pathology Protein Transport / genetics RNA Interference / physiology Subcellular Fractions / metabolism Subcellular Fractions / ultrastructure Vesicular Transport Proteins / genetics* alpha-Synuclein / metabolism*
IF 5.332
Times Cited 91
DNA material D-HA (RDB02139)