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.
authors.affiliation: Department of NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
authors.forename: Guowei
authors.initials: G
authors.lastname: Yin
authors.affiliation: Department of Neurodegeneration and Restorative Research, University Medicine Göttingen, Göttingen, Germany; DFG Research Center Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany.
authors.forename: Tomas
authors.initials: T
authors.lastname: Lopes da Fonseca
authors.affiliation: Department of Neurodegeneration and Restorative Research, University Medicine Göttingen, Göttingen, Germany; DFG Research Center Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany.
authors.forename: Sibylle E
authors.initials: SE
authors.lastname: Eisbach
authors.affiliation: Department of Genetics, University of Leicester, Leicester LE1 7RH, UK.
authors.forename: Ane Martín
authors.initials: AM
authors.lastname: Anduaga
authors.affiliation: Department of Genetics, University of Leicester, Leicester LE1 7RH, UK.
authors.forename: Carlo
authors.initials: C
authors.lastname: Breda
authors.affiliation: Max Planck for Structural Biology, Chemistry and Molecular Biophysics of Rosario (MPLbioR), Universidad Nacional de Rosario, IBR-CONICET, Ocampo y Esmeralda, 2000 Rosario, Argentina.
authors.forename: Maria L
authors.initials: ML
authors.lastname: Orcellet
authors.affiliation: Department of Neurodegeneration and Restorative Research, University Medicine Göttingen, Göttingen, Germany; DFG Research Center Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany.
authors.forename: Éva M
authors.initials: ÉM
authors.lastname: Szegő
authors.affiliation: Department of Neurodegeneration and Restorative Research, University Medicine Göttingen, Göttingen, Germany; DFG Research Center Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany.
authors.forename: Patricia
authors.initials: P
authors.lastname: Guerreiro
authors.affiliation: Department of Neurodegeneration and Restorative Research, University Medicine Göttingen, Göttingen, Germany; DFG Research Center Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany.
authors.forename: Diana F
authors.initials: DF
authors.lastname: Lázaro
authors.affiliation: Dept. Molecular Microbiology and Genetics, Institute of Microbiology & Genetics, Georg-August-Universität Göttingen, D-37077 Göttingen, Germany; DFG Research Center Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany.
authors.forename: Gerhard H
authors.initials: GH
authors.lastname: Braus
authors.affiliation: Max Planck for Structural Biology, Chemistry and Molecular Biophysics of Rosario (MPLbioR), Universidad Nacional de Rosario, IBR-CONICET, Ocampo y Esmeralda, 2000 Rosario, Argentina.
authors.forename: Claudio O
authors.initials: CO
authors.lastname: Fernandez
authors.affiliation: Department of NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Griesinger
authors.affiliation: Department of NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Becker
authors.affiliation: Max-Planck-Institute of Molecular Physiology, Department of Physical Biochemistry, Dortmund 44227, Germany.
authors.forename: Roger S
authors.initials: RS
authors.lastname: Goody
authors.affiliation: Center for Integrated Protein Science Munich, Chemistry Department, Technische Universität München, Lichtenbergstr. 4, 85748 Garching, Germany; Max-Planck-Institute of Molecular Physiology, Department of Physical Biochemistry, Dortmund 44227, Germany.
authors.forename: Aymelt
authors.initials: A
authors.lastname: Itzen
authors.affiliation: Department of Genetics, University of Leicester, Leicester LE1 7RH, UK.
authors.forename: Flaviano
authors.initials: F
authors.lastname: Giorgini
authors.affiliation: Department of Neurodegeneration and Restorative Research, University Medicine Göttingen, Göttingen, Germany; DFG Research Center Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany. Electronic address: tiago.outeiro@med.uni-goettingen.de.
authors.forename: Tiago F
authors.initials: TF
authors.lastname: Outeiro
authors.affiliation: Department of NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany; German Center for Neurodegenerative Diseases (DZNE), D-37077 Göttingen, Germany; DFG Research Center Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany. Electronic address: markus.zweckstetter@dzne.de.
authors.forename: Markus
authors.initials: M
authors.lastname: Zweckstetter
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001921:Brain / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster; D004926:Escherichia coli; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D009069:Movement Disorders / Q000503:physiopathology; D009154:Mutation; D009474:Neurons / Q000502:physiology; D010766:Phosphorylation; D011485:Protein Binding; D051381:Rats; D013574:Synaptosomes / Q000378:metabolism; D051844:alpha-Synuclein / Q000737:chemistry* / Q000378:metabolism*; D020691:rab GTP-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; D051844:alpha-Synuclein; D020558:GTP Phosphohydrolases; C000596969:Rab8 protein, Drosophila; C082377:RAB8A protein, human; D020691:rab GTP-Binding Proteins
keywords: Aggregation; Parkinson's disease; Phosphorylation; Rab GTPase; α-Synuclein