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

Lookup NU author(s): Professor Tiago Outeiro

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Abstract

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. © 2014 Elsevier Inc.


Publication metadata

Author(s): Yin G, Lopes da Fonseca T, Eisbach SE, Anduaga AM, Breda C, Orcellet ML, Szego TM, Guerreiro P, Lazaro DF, Braus GH, Fernandez CO, Griesinger C, Becker S, Goody RS, Itzen A, Giorgini F, Outeiro TF, Zweckstetter M

Publication type: Article

Publication status: Published

Journal: Neurobiology of Disease

Year: 2014

Volume: 70

Pages: 149-161

Online publication date: 28/06/2014

Acceptance date: 22/06/2014

ISSN (print): 0969-9961

ISSN (electronic): 1095-953X

Publisher: Academic Press Inc.

URL: https://doi.org/10.1016/j.nbd.2014.06.018

DOI: 10.1016/j.nbd.2014.06.018

PubMed id: 24983211


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