Please use this identifier to cite or link to this item: http://hdl.handle.net/2381/39132
Title: α-Synuclein interacts with the switch region of Rab8a in a Ser129 phosphorylation-dependent manner.
Authors: Yin, G.
Lopes da Fonseca, T.
Eisbach, S. E.
Anduaga, Ane Martín
Breda, Carlo
Orcellet, M. L.
Szegő, É. M.
Guerreiro, P.
Lázaro, D. F.
Braus, G. H.
Fernandez, C. O.
Griesinger, C.
Becker, S.
Goody, R. S.
Itzen, A.
Giorgini, Flaviano
Outeiro, T. F.
Zweckstetter, M.
First Published: 28-Oct-2014
Publisher: Elsevier for Academic Press
Citation: Neurobiology of Disease, 2014, 70, pp. 149-161
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.
DOI Link: 10.1016/j.nbd.2014.06.018
ISSN: 0969-9961
eISSN: 1095-953X
Links: http://www.sciencedirect.com/science/article/pii/S096999611400182X
http://hdl.handle.net/2381/39132
Version: Post-print
Status: Peer-reviewed
Type: Journal Article
Rights: Creative Commons “Attribution Non-Commercial No Derivatives” licence CC BY-NC-ND, further details of which can be found via the following link: http://creativecommons.org/licenses/by-nc-nd/4.0/ Archived with reference to SHERPA/RoMEO and publisher website.
Description: Supplementary data to this article can be found online at http://dx.doi.org/10.1016/j.nbd.2014.06.018.
Appears in Collections:Published Articles, Dept. of Genetics

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