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

NEUROBIOLOGY OF DISEASE

卷:70

Article

Yin, Guowei¹  Da Fonseca, Tomas Lopes^4,5  Eisbach, Sibylle E.^4,5  Anduaga, Ane Martin⁹  Breda, Carlo⁹  Orcellet, Maria L.⁶  Szego, Eva M.^4,5  Guerreiro, Patricia^4,5  Lazar, Diana F.^4,5  Braus, Gerhard H.^3,5  Fernandez, Claudio⁶  Griesinger, Christian¹  Goody, Roger S.^1,8  Itzen, Aymelt^7,8  Giorgini, Flaviano⁹  Outeiro, Tiago F.^4,5  Zweckstetter, Markus^1,2,4,5 

[1] Max Planck Inst Biophys Chem, Dept NMR Based Struct Biol, D-37077 Gottingen, Germany

[2] German Ctr Neurodegenerat Dis DZNE, D-37077 Gottingen, Germany

[3] Univ Gottingen, Inst Microbiol & Genet, Dept Mol Microbiol & Genet, D-37077 Gottingen, Germany

[4] Univ Med Gottingen, Dept Neurodegenerat & Restorat Res, Gottingen, Germany

[5] DFG Res Ctr Nanoscale Microscopy & Mol Physiol Br, Gottingen, Germany

[6] Univ Nacl Rosario, CONICET, IBR, Max Planck Struct Biol Chem & Mol Biophys Rosario, RA-2000 Rosario, Santa Fe, Argentina

[7] Tech Univ Munich, Ctr Integrated Prot Sci Munich, Dept Chem, D-85748 Garching, Germany

[8] Max Planck Inst Mol Physiol, Dept Phys Biochem, D-44227 Dortmund, Germany

[9] Univ Leicester, Dept Genet, Leicester LE1 7RH, Leics, England

关键词: alpha-Synuclein;    Aggregation;    Parkinson's disease;    Phosphorylation;    Rab GTPase;   

DOI  :  10.1016/j.nbd.2014.06.018

来源: Elsevier

【 摘 要 】

Alpha-synuclein (alpha S) misfolding is associated with Parkinson's disease (PD) but little is known about the mechanisms underlying alpha S 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 alpha S in rodent brain. NMR spectroscopy reveals that the C-terminus of alpha S binds to the functionally important switch region as well as the C-terminal tail of Rab8a. In line with a direct Rab8a/alpha S interaction, Rab8a enhanced alpha S aggregation and reduced alpha S-induced cellular toxicity. In addition, Rab8 - the Drosophila ortholog of Rab8a - ameliorated alpha S-oligomer specific locomotor impairment and neuron loss in fruit flies. In support of the pathogenic relevance of the alpha S-Rab8a interaction, phosphorylation of alpha S at S129 enhanced binding to Rab8a, increased formation of insoluble alpha S aggregates and reduced cellular toxicity. Our study provides novel mechanistic insights into the interplay of the GTPase Rab8a and alpha S cytotoxicity, and underscores the therapeutic potential of targeting this interaction. (C) 2014 Elsevier Inc. All rights reserved.

【 授权许可】

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