| First Author | Yin G | Year | 2014 |
| Journal | Neurobiol Dis | Volume | 70 |
| Pages | 149-61 | PubMed ID | 24983211 |
| Mgi Jnum | J:215464 | Mgi Id | MGI:5605417 |
| Doi | 10.1016/j.nbd.2014.06.018 | Citation | Yin G, et al. (2014) alpha-Synuclein interacts with the switch region of Rab8a in a Ser129 phosphorylation-dependent manner. Neurobiol Dis 70:149-61 |
| abstractText | Alpha-synuclein (alphaS) misfolding is associated with Parkinson's disease (PD) but little is known about the mechanisms underlying alphaS 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 alphaS in rodent brain. NMR spectroscopy reveals that the C-terminus of alphaS binds to the functionally important switch region as well as the C-terminal tail of Rab8a. In line with a direct Rab8a/alphaS interaction, Rab8a enhanced alphaS aggregation and reduced alphaS-induced cellular toxicity. In addition, Rab8 - the Drosophila ortholog of Rab8a - ameliorated alphaS-oligomer specific locomotor impairment and neuron loss in fruit flies. In support of the pathogenic relevance of the alphaS-Rab8a interaction, phosphorylation of alphaS at S129 enhanced binding to Rab8a, increased formation of insoluble alphaS aggregates and reduced cellular toxicity. Our study provides novel mechanistic insights into the interplay of the GTPase Rab8a and alphaS cytotoxicity, and underscores the therapeutic potential of targeting this interaction. |
