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

GUOWEI YIN; TOMAS LOPES DA FONSECA; SIBYLLE E. EISBACH; ANE MARTÍN ANDUAGA; CARLO BREDA; MARIA L. ORCELLET; ÉVA M. SZEGO; PATRICIA GUERREIRO ; DIANA LAZARO; GERHARD H. BRAUS; CLAUDIO O. FERNANDEZ; CHRISTIAN GRIESINGER; STEFAN BECKER; ROGER S. GOODY; AYMELT ITZENG; FLAVIANO GIORGINI ; TIAGO F. OUTEIRO; MARKUS ZWECKSTETTER

NEUROBIOLOGY OF DISEASE

ACADEMIC PRESS INC ELSEVIER SCIENCE

Año: 2014

0969-9961

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