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

Emiko Miura, Takafumi Hasegawa, Masatoshi Konno, Mari Suzuki, Naoto Sugeno, Nobuhiro Fujikake, Sven Geisler, Mitsuaki Tabuchi, Ryuji Oshima, Akio Kikuchi, Toru Baba, Keiji Wada, Yoshitaka Nagai, Atsushi Takeda, Masashi Aoki

Research output: Contribution to journalArticle

97 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1-13
Number of pages13
JournalNeurobiology of Disease
Volume71
DOIs
Publication statusPublished - 2014 Nov

Keywords

  • Cathepsin D
  • Lysosome
  • Parkinson's disease
  • Retromer
  • VPS35
  • Vesicular transport
  • α-Synuclein

ASJC Scopus subject areas

  • Neurology

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