title: VPS35 dysfunction impairs lysosomal degradation of α-synuclein and exacerbates neurotoxicity in a Drosophila model of Parkinson's disease.
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.
authors.affiliation: Division of Neurology, Department of Neuroscience & Sensory Organs, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan.
authors.forename: Emiko
authors.initials: E
authors.lastname: Miura
authors.affiliation: Division of Neurology, Department of Neuroscience & Sensory Organs, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan. Electronic address: thasegawa@med.tohoku.ac.jp.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Hasegawa
authors.affiliation: Division 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.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Konno
authors.affiliation: Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Kodaira 187-8502, Japan.
authors.forename: Mari
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Division of Neurology, Department of Neuroscience & Sensory Organs, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Sugeno
authors.affiliation: Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Kodaira 187-8502, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Fujikake
authors.affiliation: Laboratory 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.
authors.forename: Sven
authors.initials: S
authors.lastname: Geisler
authors.affiliation: Laboratory of Applied Molecular Cell Biology, Faculty of Agriculture, Kagawa University, Kagawa 761-0795, Japan.
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Tabuchi
authors.affiliation: Division of Neurology, Department of Neuroscience & Sensory Organs, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan.
authors.forename: Ryuji
authors.initials: R
authors.lastname: Oshima
authors.affiliation: Division of Neurology, Department of Neuroscience & Sensory Organs, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Kikuchi
authors.affiliation: Division of Neurology, Department of Neuroscience & Sensory Organs, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Baba
authors.affiliation: Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Kodaira 187-8502, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Wada
authors.affiliation: Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Kodaira 187-8502, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Nagai
authors.affiliation: Division 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.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takeda
authors.affiliation: Division of Neurology, Department of Neuroscience & Sensory Organs, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Aoki
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002402:Cathepsin D / Q000378:metabolism; D004195:Disease Models, Animal; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics*; D005123:Eye / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D008124:Locomotion / Q000235:genetics; D008247:Lysosomes / Q000378:metabolism*; D009154:Mutation / Q000235:genetics*; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D021381:Protein Transport / Q000235:genetics; D034622:RNA Interference / Q000502:physiology; D013347:Subcellular Fractions / Q000378:metabolism / Q000648:ultrastructure; D033921:Vesicular Transport Proteins / Q000235:genetics*; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; D033921:Vesicular Transport Proteins; C527271:Vps35 protein, Drosophila; D051844:alpha-Synuclein; D002402:Cathepsin D
keywords: Cathepsin D; Lysosome; Parkinson's disease; Retromer; VPS35; Vesicular transport; α-Synuclein