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

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

Neurobiology of disease, 2014-11, Vol.71, p.1-13 [Periódico revisado por pares]

United States: Elsevier Inc

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VPS35 dysfunction impairs lysosomal degradation of α-synuclein and exacerbates neurotoxicity in a Drosophila model of Parkinson's disease
Autor: Miura, Emiko ; Hasegawa, Takafumi ; Konno, Masatoshi ; Suzuki, Mari ; Sugeno, Naoto ; Fujikake, Nobuhiro ; Geisler, Sven ; Tabuchi, Mitsuaki ; Oshima, Ryuji ; Kikuchi, Akio ; Baba, Toru ; Wada, Keiji ; Nagai, Yoshitaka ; Takeda, Atsushi ; Aoki, Masashi
Assuntos: alpha-Synuclein - metabolism ; Animals ; Animals, Genetically Modified ; Brain - metabolism ; Brain - pathology ; Cathepsin D ; Cathepsin D - metabolism ; Disease Models, Animal ; Drosophila ; Drosophila Proteins - genetics ; Eye - metabolism ; Eye - pathology ; Gene Expression Regulation - genetics ; HEK293 Cells ; Humans ; Immunoprecipitation ; Locomotion - genetics ; Lysosome ; Lysosomes - metabolism ; Mutation - genetics ; Neurology ; Parkinson Disease - genetics ; Parkinson Disease - metabolism ; Parkinson Disease - pathology ; Parkinson's disease ; Protein Transport - genetics ; Retromer ; RNA Interference - physiology ; Subcellular Fractions - metabolism ; Subcellular Fractions - ultrastructure ; Vesicular transport ; Vesicular Transport Proteins - genetics ; VPS35 ; α-Synuclein
É parte de: Neurobiology of disease, 2014-11, Vol.71, p.1-13
Descrição: 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.
Editor: United States: Elsevier Inc
Idioma: Inglês

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

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

United States: Elsevier Inc

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