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A systematic RNAi screen reveals involvement of endocytic pathway in neuronal dysfunction in alpha-synuclein transgenic C. elegans.
Kuwahara, Tomoki; Koyama, Akihiko; Koyama, Shingo; Yoshina, Sawako; Ren, Chang-Hong; Kato, Takeo; Mitani, Shohei; Iwatsubo, Takeshi.
Afiliação
  • Kuwahara T; Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan.
Hum Mol Genet ; 17(19): 2997-3009, 2008 Oct 01.
Article em En | MEDLINE | ID: mdl-18617532
ABSTRACT
Mutations or multiplications in alpha-synuclein gene cause familial forms of Parkinson disease or dementia with Lewy bodies (LB), and the deposition of wild-type alpha-synuclein as LB occurs as a hallmark lesion of these disorders, collectively referred to as synucleinopathies, implicating alpha-synuclein in the pathogenesis of synucleinopathy. To identify modifier genes of alpha-synuclein-induced neurotoxicity, we conducted an RNAi screen in transgenic C. elegans (Tg worms) that overexpress human alpha-synuclein in a pan-neuronal manner. To enhance the RNAi effect in neurons, we crossed alpha-synuclein Tg worms with an RNAi-enhanced mutant eri-1 strain. We tested RNAi of 1673 genes related to nervous system or synaptic functions, and identified 10 genes that, upon knockdown, caused severe growth/motor abnormalities selectively in alpha-synuclein Tg worms. Among these were four genes (i.e. apa-2, aps-2, eps-8 and rab-7) related to the endocytic pathway, including two subunits of AP-2 complex. Consistent with the results by RNAi, crossing alpha-synuclein Tg worms with an aps-2 mutant resulted in severe growth arrest and motor dysfunction. alpha-Synuclein Tg worms displayed a decreased touch sensitivity upon RNAi of genes involved in synaptic vesicle endocytosis, and they also showed impaired neuromuscular transmission, suggesting that overexpression of alpha-synuclein caused a failure in uptake or recycling of synaptic vesicles. Furthermore, knockdown of apa-2, an AP-2 subunit, caused an accumulation of phosphorylated alpha-synuclein in neuronal cell bodies, mimicking synucleinopathy. Collectively, these findings raise a novel pathogenic link between endocytic pathway and alpha-synuclein-induced neurotoxicity in synucleinopathy.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Vesículas Sinápticas / Caenorhabditis elegans / Doenças Neurodegenerativas / Interferência de RNA / Endocitose / Alfa-Sinucleína / Neurônios Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: Hum Mol Genet Assunto da revista: BIOLOGIA MOLECULAR / GENETICA MEDICA Ano de publicação: 2008 Tipo de documento: Article País de afiliação: Japão

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Vesículas Sinápticas / Caenorhabditis elegans / Doenças Neurodegenerativas / Interferência de RNA / Endocitose / Alfa-Sinucleína / Neurônios Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: Hum Mol Genet Assunto da revista: BIOLOGIA MOLECULAR / GENETICA MEDICA Ano de publicação: 2008 Tipo de documento: Article País de afiliação: Japão