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

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journal contribution
posted on 11.01.2017, 11:53 by G. Yin, T. Lopes da Fonseca, S. E. Eisbach, Ane Martín Anduaga, Carlo Breda, M. L. Orcellet, É. M. Szegő, P. Guerreiro, D. F. Lázaro, G. H. Braus, C. O. Fernandez, C. Griesinger, S. Becker, R. S. Goody, A. Itzen, Flaviano Giorgini, T. F. Outeiro, M. Zweckstetter
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.

Funding

This work was supported by the BMBF (NGFN-Plus 01GS08190 to M.Z.). Tomás Lopes da Fonseca is supported by a fellowship from the Fundação para a Ciência e a Tecnologia, Portugal (SFRH/BD/74881/2010). Work in the laboratory of Flaviano Giorgini is supported by Parkinson's UK (G-1203). TFO is supported by the DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain.

History

Citation

Neurobiology of Disease, 2014, 70, pp. 149-161

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/MBSP Non-Medical Departments/Department of Genetics

Version

AM (Accepted Manuscript)

Published in

Neurobiology of Disease

Publisher

Elsevier for Academic Press

issn

0969-9961

eissn

1095-953X

Acceptance date

22/06/2014

Available date

11/01/2017

Publisher version

http://www.sciencedirect.com/science/article/pii/S096999611400182X

Notes

Supplementary data to this article can be found online at http://dx.doi.org/10.1016/j.nbd.2014.06.018.

Language

en