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

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α-Synuclein interacts with the switch region of Rab8a in a Ser129 phosphorylation-dependent manner. / Yin, Guowei; Lopes da Fonseca, Tomas; Eisbach, Sibylle E; Anduaga, Ane Martín; Breda, Carlo; Orcellet, Maria L; Szegő, Éva M; Guerreiro, Patricia; Lázaro, Diana F; Braus, Gerhard H; Fernandez, Claudio O; Griesinger, Christian; Becker, Stefan; Goody, Roger S; Itzen, Aymelt; Giorgini, Flaviano; Outeiro, Tiago F; Zweckstetter, Markus.

in: NEUROBIOL DIS, Jahrgang 70, 10.2014, S. 149-61.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Yin, G, Lopes da Fonseca, T, Eisbach, SE, Anduaga, AM, Breda, C, Orcellet, ML, Szegő, ÉM, Guerreiro, P, Lázaro, DF, Braus, GH, Fernandez, CO, Griesinger, C, Becker, S, Goody, RS, Itzen, A, Giorgini, F, Outeiro, TF & Zweckstetter, M 2014, 'α-Synuclein interacts with the switch region of Rab8a in a Ser129 phosphorylation-dependent manner', NEUROBIOL DIS, Jg. 70, S. 149-61. https://doi.org/10.1016/j.nbd.2014.06.018

APA

Yin, G., Lopes da Fonseca, T., Eisbach, S. E., Anduaga, A. M., Breda, C., 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, F., Outeiro, T. F., & Zweckstetter, M. (2014). α-Synuclein interacts with the switch region of Rab8a in a Ser129 phosphorylation-dependent manner. NEUROBIOL DIS, 70, 149-61. https://doi.org/10.1016/j.nbd.2014.06.018

Vancouver

Yin G, Lopes da Fonseca T, Eisbach SE, Anduaga AM, Breda C, Orcellet ML et al. α-Synuclein interacts with the switch region of Rab8a in a Ser129 phosphorylation-dependent manner. NEUROBIOL DIS. 2014 Okt;70:149-61. https://doi.org/10.1016/j.nbd.2014.06.018

Bibtex

@article{86b996afaf414c2e8b93e98fc239cd28,
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 = "Animals, Animals, Genetically Modified, Brain, Cell Line, Tumor, Cell Survival, Drosophila Proteins, Drosophila melanogaster, Escherichia coli, GTP Phosphohydrolases, Humans, Mice, Models, Molecular, Movement Disorders, Mutation, Neurons, Phosphorylation, Protein Binding, Rats, Synaptosomes, alpha-Synuclein, rab GTP-Binding Proteins, Journal Article, Research Support, Non-U.S. Gov't",
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 Szeg{\H o}, {{\'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 = "Copyright {\textcopyright} 2014 Elsevier Inc. All rights reserved.",
year = "2014",
month = oct,
doi = "10.1016/j.nbd.2014.06.018",
language = "English",
volume = "70",
pages = "149--61",
journal = "NEUROBIOL DIS",
issn = "0969-9961",
publisher = "Academic Press Inc.",

}

RIS

TY - JOUR

T1 - α-Synuclein interacts with the switch region of Rab8a in a Ser129 phosphorylation-dependent manner

AU - Yin, Guowei

AU - Lopes da Fonseca, Tomas

AU - Eisbach, Sibylle E

AU - Anduaga, Ane Martín

AU - Breda, Carlo

AU - Orcellet, Maria L

AU - Szegő, Éva M

AU - Guerreiro, Patricia

AU - Lázaro, Diana F

AU - Braus, Gerhard H

AU - Fernandez, Claudio O

AU - Griesinger, Christian

AU - Becker, Stefan

AU - Goody, Roger S

AU - Itzen, Aymelt

AU - Giorgini, Flaviano

AU - Outeiro, Tiago F

AU - Zweckstetter, Markus

N1 - Copyright © 2014 Elsevier Inc. All rights reserved.

PY - 2014/10

Y1 - 2014/10

N2 - 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.

AB - 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.

KW - Animals

KW - Animals, Genetically Modified

KW - Brain

KW - Cell Line, Tumor

KW - Cell Survival

KW - Drosophila Proteins

KW - Drosophila melanogaster

KW - Escherichia coli

KW - GTP Phosphohydrolases

KW - Humans

KW - Mice

KW - Models, Molecular

KW - Movement Disorders

KW - Mutation

KW - Neurons

KW - Phosphorylation

KW - Protein Binding

KW - Rats

KW - Synaptosomes

KW - alpha-Synuclein

KW - rab GTP-Binding Proteins

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1016/j.nbd.2014.06.018

DO - 10.1016/j.nbd.2014.06.018

M3 - SCORING: Journal article

C2 - 24983211

VL - 70

SP - 149

EP - 161

JO - NEUROBIOL DIS

JF - NEUROBIOL DIS

SN - 0969-9961

ER -