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

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Neurobiol Dis 2014 Jun; 70C:149-161

Authors: Guowei Yin, Tomas Lopes da Fonseca, Sibylle E Eisbach, Ane Martín Anduaga, Carlo Breda, Maria L Orcellet, Eva M Szeg?, Patricia Guerreiro, Diana F Lázaro, Gerhard H Braus, Claudio O Fernandez, Christian Griesinger, Stefan Becker, Roger S Goody, Aymelt Itzen, Flaviano Giorgini, Tiago F Outeiro, Markus Zweckstetter

Alpha-synuclein (?S) misfolding is associated with Parkinson's disease (PD) but little is known about the mechanisms underlying ?S 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 ?S in rodent brain. NMR spectroscopy reveals that the C-terminus of ?S binds to the functionally important switch region as well as the C-terminal tail of Rab8a. In line with a direct Rab8a/?S interaction, Rab8a enhanced ?S aggregation and reduced ?S-induced cellular toxicity. In addition, Rab8 - the Drosophila ortholog of Rab8a - ameliorated ?S-oligomer specific locomotor impairment and neuron loss in fruit flies. In support of the pathogenic relevance of the ?S-Rab8a interaction, phosphorylation of ?S at S129 enhanced binding to Rab8a, increased formation of insoluble ?S aggregates and reduced cellular toxicity. Our study provides novel mechanistic insights into the interplay of the GTPase Rab8a and ?S cytotoxicity, and underscores the therapeutic potential of targeting this interaction.

PMID: 24983211 [PubMed - as supplied by publisher]

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