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VPS35 dysfunction impairs lysosomal degradation of {Alpha}-synuclein and exacerbates neurotoxicity in a Drosophila model of Parkinson’s disease.

Miura E1, Hasegawa T2, Konno M3, Suzuki M4, Sugeno N1, Fujikake N4, Geisler S5, Tabuchi M6, Oshima R1, Kikuchi A1, Baba T1, Wada K4, Nagai Y4, Takeda A7, Aoki M1.

Neurobiol Dis. 2014;71:1-13.

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1Division of Neurology, Department of Neuroscience & Sensory Organs, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan.

2Division of Neurology, Department of Neuroscience & Sensory Organs, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan. Electronic address: [email protected]

3Division of Neurology, Department of Neuroscience & Sensory Organs, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan; Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Kodaira 187-8502, Japan.

4Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Kodaira 187-8502, Japan.

5Laboratory of Functional Neurogenetics, Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, German Centre for Neurodegenerative Diseases (DZNE), 72076 Tübingen, Germany.

6Laboratory of Applied Molecular Cell Biology, Faculty of Agriculture, Kagawa University, Kagawa 761-0795, Japan.

7Division of Neurology, Department of Neuroscience & Sensory Organs, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan; Department of Neurology, National Hospital Organization Sendai-Nishitaga Hospital, Sendai 982-8555, Japan.

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 thelysosomal 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.

Copyright © 2014 Elsevier Inc. All rights reserved.

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Figure Legend

Schematic illustrations of retromer-mediated trafficking of Cathepsin D (CTSD) and possible contribution to lysosomal {Alpha}-synuclein ({Alpha}SYN) degradation. VPS35, a critical component of the retromer complex, mediates retrograde transport of cargo protein (CI-MPR) from endosome to the trans-Golgi network (TGN). Under physiological condition (upper panel), upon arrival in the Golgi apparatus, newly synthesized CTSD precursor is specifically modified with mannose-6-phosphate (M6P) residues, which are recognized by CI-MPR in the TGN. CI-MPR escorts CTSD into endosomes, in which the CTSD are released for further transport to lysosomes. During this process, CTSD is activated by the proteolytic cleavage of the signal peptide sequence. The retromer retrieves the unoccupied MPRs from endosomes to the TGN, where they participate in further cycles of CTSD sorting. If the retromer function is perturbed (lower panel), the retromer fails to retrieve CI-MPR from the endosome to the TGN, which results in increased secretion of precursor CTSD as well as the impaired trafficking of CTSD. As a consequence, the amount of mature CTSD in the lysosome is decreased, which increases the accumulation of toxic {Alpha}SYN species, thereby influences the neurodegenerative process linked to Parkinson’s disease.

VPS35 dysfunction impairs lysosomal degradation of {Alpha}-synuclein and exacerbates neurotoxicity in a Drosophila model of Parkinson's disease. Global Medical Discovery