VPS35 dysfunction impairs lysosomal degradation of α-synuclein and exacerbates neurotoxicity in a Drosophila model of Parkinson's disease
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 tur...
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Elsevier
2014-11-01
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Series: | Neurobiology of Disease |
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Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996114002150 |
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doaj-e15eaafce8ab43178246b6eff6d16a8d |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
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 |
spellingShingle |
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 VPS35 dysfunction impairs lysosomal degradation of α-synuclein and exacerbates neurotoxicity in a Drosophila model of Parkinson's disease Neurobiology of Disease Parkinson's disease VPS35 α-Synuclein Retromer Cathepsin D Lysosome |
author_facet |
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 |
author_sort |
Emiko Miura |
title |
VPS35 dysfunction impairs lysosomal degradation of α-synuclein and exacerbates neurotoxicity in a Drosophila model of Parkinson's disease |
title_short |
VPS35 dysfunction impairs lysosomal degradation of α-synuclein and exacerbates neurotoxicity in a Drosophila model of Parkinson's disease |
title_full |
VPS35 dysfunction impairs lysosomal degradation of α-synuclein and exacerbates neurotoxicity in a Drosophila model of Parkinson's disease |
title_fullStr |
VPS35 dysfunction impairs lysosomal degradation of α-synuclein and exacerbates neurotoxicity in a Drosophila model of Parkinson's disease |
title_full_unstemmed |
VPS35 dysfunction impairs lysosomal degradation of α-synuclein and exacerbates neurotoxicity in a Drosophila model of Parkinson's disease |
title_sort |
vps35 dysfunction impairs lysosomal degradation of α-synuclein and exacerbates neurotoxicity in a drosophila model of parkinson's disease |
publisher |
Elsevier |
series |
Neurobiology of Disease |
issn |
1095-953X |
publishDate |
2014-11-01 |
description |
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. |
topic |
Parkinson's disease VPS35 α-Synuclein Retromer Cathepsin D Lysosome |
url |
http://www.sciencedirect.com/science/article/pii/S0969996114002150 |
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doaj-e15eaafce8ab43178246b6eff6d16a8d2021-03-22T12:41:42ZengElsevierNeurobiology of Disease1095-953X2014-11-0171113VPS35 dysfunction impairs lysosomal degradation of α-synuclein and exacerbates neurotoxicity in a Drosophila model of Parkinson's diseaseEmiko Miura0Takafumi Hasegawa1Masatoshi Konno2Mari Suzuki3Naoto Sugeno4Nobuhiro Fujikake5Sven Geisler6Mitsuaki Tabuchi7Ryuji Oshima8Akio Kikuchi9Toru Baba10Keiji Wada11Yoshitaka Nagai12Atsushi Takeda13Masashi Aoki14Division of Neurology, Department of Neuroscience & Sensory Organs, Tohoku University Graduate School of Medicine, Sendai 980-8574, JapanDivision of Neurology, Department of Neuroscience & Sensory Organs, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan; Corresponding author at: Division of Neurology, Department of Neuroscience & Sensory Organs, Tohoku University Graduate School of Medicine, 1-1, Seiryomachi, Aobaku, Sendai, Miyagi 980-8574, Japan. Fax: +81 22 717 7192.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, JapanDepartment of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Kodaira 187-8502, JapanDivision of Neurology, Department of Neuroscience & Sensory Organs, Tohoku University Graduate School of Medicine, Sendai 980-8574, JapanDepartment of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Kodaira 187-8502, JapanLaboratory of Functional Neurogenetics, Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, German Centre for Neurodegenerative Diseases (DZNE), 72076 Tübingen, GermanyLaboratory of Applied Molecular Cell Biology, Faculty of Agriculture, Kagawa University, Kagawa 761-0795, JapanDivision of Neurology, Department of Neuroscience & Sensory Organs, Tohoku University Graduate School of Medicine, Sendai 980-8574, JapanDivision of Neurology, Department of Neuroscience & Sensory Organs, Tohoku University Graduate School of Medicine, Sendai 980-8574, JapanDivision of Neurology, Department of Neuroscience & Sensory Organs, Tohoku University Graduate School of Medicine, Sendai 980-8574, JapanDepartment of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Kodaira 187-8502, JapanDepartment of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Kodaira 187-8502, JapanDivision 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, JapanDivision of Neurology, Department of Neuroscience & Sensory Organs, Tohoku University Graduate School of Medicine, Sendai 980-8574, JapanMutations 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.http://www.sciencedirect.com/science/article/pii/S0969996114002150Parkinson's diseaseVPS35α-SynucleinRetromerCathepsin DLysosome |