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

• Main Authors: Guowei Yin, Tomas Lopes da Fonseca, Sibylle E. Eisbach, Ane Martín Anduaga, Carlo Breda, Maria L. Orcellet, Éva M. Szegő, 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
• Format: Article
• Language: English
• Published: Elsevier 2014-10-01
• Series: Neurobiology of Disease
• Subjects: α-Synuclein; Aggregation; Parkinson's disease; Phosphorylation; Rab GTPase
• Online Access: http://www.sciencedirect.com/science/article/pii/S096999611400182X

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.