@article{4277b208e0024d9e9f92103cebc6b176,
title = "α-Synuclein interacts with the switch region of Rab8a in a Ser129 phosphorylation-dependent manner",
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.",
keywords = "Aggregation, Parkinson's disease, Phosphorylation, Rab GTPase, α-Synuclein",
author = "Guowei Yin and {Lopes da Fonseca}, Tomas and Eisbach, {Sibylle E.} and Anduaga, {Ane Mart{\'i}n} and Carlo Breda and Orcellet, {Maria L.} and Szego, {{\'E}va M.} and Patricia Guerreiro and L{\'a}zaro, {Diana F.} and Braus, {Gerhard H.} and Fernandez, {Claudio O.} and Christian Griesinger and Stefan Becker and Goody, {Roger S.} and Aymelt Itzen and Flaviano Giorgini and Outeiro, {Tiago F.} and Markus Zweckstetter",
note = "Funding Information: We thank Dr. Dietmar Riedel and Gudrun Heim for electron micrographs, Sebastian Wolff and Karin Giller for αS sample preparation, Kerstin Overkamp for peptide synthesis, Nathalie Bleimling for Rab8a sample preparation and Pinar Karpinar for help in initial NMR measurements. The GFP-Rab8a plasmid was kindly provided by Dr. Mikael Simons. This work was supported by the BMBF (NGFN-Plus 01GS08190 to M.Z.). Tom{\'a}s Lopes da Fonseca is supported by a fellowship from the Funda{\c c}{\~a}o para a Ci{\^e}ncia 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. The authors declare that they have no conflict of interest.",
year = "2014",
month = oct,
doi = "10.1016/j.nbd.2014.06.018",
language = "English",
volume = "70",
pages = "149--161",
journal = "Neurobiology of Disease",
issn = "0969-9961",
publisher = "Academic Press Inc.",
}