α-Synuclein interacts with the switch region of Rab8a in a Ser129 phosphorylation-dependent manner

Alpha-synuclein (αS) misfolding is associated with Parkinson's disease (PD) but little is known about the mechanisms underlying αS toxicity. Increasing evidence suggests that defects in membrane transport play an important role in neuronal dysfunction. Here we demonstrate that the GTPase Rab8a...

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Detalles Bibliográficos
Autores: Yin, Guowei, Lopes da Fonseca, Tomas, Eisbach, Sibylle E., Anduaga, Ane Martin, Breda, Carlo, Orcellet, Maria Laura, Szegő, Eva M., Guerreiro, Patria, Lázaro, Diana F., Braus, Gerhard H., Fernandez, Claudio Oscar, Griesinger, Christian, Becker, Stefan, Goody, Roger S., Itzen, Aymelt, Giorgini, Flaviano, Outeiro, Tiago F., Zweckstetter, Markus
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2014
País:Argentina
Institución:Consejo Nacional de Investigaciones Científicas y Técnicas
Repositorio:CONICET Digital (CONICET)
Idioma:inglés
OAI Identifier:oai:ri.conicet.gov.ar:11336/29424
Acceso en línea:http://hdl.handle.net/11336/29424
Access Level:acceso abierto
Palabra clave:Α-Synuclein
Aggregation
Parkinson'S Disease
Phosphorylation
Rab Gtpase
https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
Descripción
Sumario:Alpha-synuclein (αS) misfolding is associated with Parkinson's disease (PD) but little is known about the mechanisms underlying αS toxicity. Increasing evidence suggests that defects in membrane transport play an important role in neuronal dysfunction. Here we demonstrate that the GTPase Rab8a interacts with αS in rodent brain. NMR spectroscopy reveals that the C-terminus of αS binds to the functionally important switch region as well as the C-terminal tail of Rab8a. In line with a direct Rab8a/αS interaction, Rab8a enhanced αS aggregation and reduced αS-induced cellular toxicity. In addition, Rab8 – the Drosophila ortholog of Rab8a – ameliorated αS-oligomer specific locomotor impairment and neuron loss in fruit flies. In support of the pathogenic relevance of the αS–Rab8a interaction, phosphorylation of αS at S129 enhanced binding to Rab8a, increased formation of insoluble αS aggregates and reduced cellular toxicity. Our study provides novel mechanistic insights into the interplay of the GTPase Rab8a and αS cytotoxicity, and underscores the therapeutic potential of targeting this interaction.

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