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

研究成果: Article査読

115 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)1-13
ページ数13
ジャーナルNeurobiology of Disease
71
DOI
出版ステータスPublished - 2014 11

ASJC Scopus subject areas

  • 神経学

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