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

Yin, G., Lopes da Fonseca, T., Eisbach, S. E., Anduaga, A. M., Breda, C., Orcellet, M. L., et al. (2014). α-Synuclein interacts with the switch region of Rab8a in a Ser129 phosphorylation-dependent manner. Neurobiology of Disease, 70, 149-161. doi:10.1016/j.nbd.2014.06.018.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-001A-0756-A Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0029-BC29-9
Genre: Journal Article

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 Creators:
Yin, G.1, Author              
Lopes da Fonseca, T., Author
Eisbach, S. E., Author
Anduaga, A. M., Author
Breda, C., Author
Orcellet, M. L., Author
Szegő, E. M., Author
Guerreiro, P., Author
Lázaro, D. F., Author
Braus, G. H., Author
Fernandez, C. O., Author
Griesinger, C.1, Author              
Becker, S.1, Author              
Goody, R. S., Author
Itzen, A., Author
Giorgini, F., Author
Outeiro, T. F., Author
Zweckstetter, M.2, Author              
Affiliations:
1Department of NMR Based Structural Biology, MPI for biophysical chemistry, Max Planck Society, ou_578567              
2Research Group of Protein Structure Determination using NMR, MPI for biophysical chemistry, Max Planck Society, ou_578571              

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Free keywords: α-Synuclein; Aggregation; Parkinson's disease; Phosphorylation; Rab GTPase
 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.

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Language(s): eng - English
 Dates: 2014-06-282014-10
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1016/j.nbd.2014.06.018
 Degree: -

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Title: Neurobiology of Disease
Source Genre: Journal
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Publ. Info: -
Pages: - Volume / Issue: 70 Sequence Number: - Start / End Page: 149 - 161 Identifier: -