| First Author | Sancenon V | Year | 2012 |
| Journal | Hum Mol Genet | Volume | 21 |
| Issue | 11 | Pages | 2432-49 |
| PubMed ID | 22357655 | Mgi Jnum | J:183778 |
| Mgi Id | MGI:5319258 | Doi | 10.1093/hmg/dds058 |
| Citation | Sancenon V, et al. (2012) Suppression of alpha-synuclein toxicity and vesicle trafficking defects by phosphorylation at S129 in yeast depends on genetic context. Hum Mol Genet 21(11):2432-49 |
| abstractText | The aggregation of alpha-synuclein (alphaSyn) is a neuropathologic hallmark of Parkinson's disease and other synucleinopathies. In Lewy bodies, alphaSyn is extensively phosphorylated, predominantly at serine 129 (S129). Recent studies in yeast have shown that, at toxic levels, alphaSyn disrupts Rab homeostasis, causing an initial endoplasmic reticulum-to-Golgi block that precedes a generalized trafficking collapse. However, whether alphaSyn phosphorylation modulates trafficking defects has not been evaluated. Here, we show that constitutive expression of alphaSyn in yeast impairs late-exocytic, early-endocytic and/or recycling trafficking. Although members of the casein kinase I (CKI) family phosphorylate alphaSyn at S129, they attenuate alphaSyn toxicity and trafficking defects by an S129 phosphorylation-independent mechanism. Surprisingly, phosphorylation of S129 modulates alphaSyn toxicity and trafficking defects in a manner strictly determined by genetic background. Abnormal endosome morphology, increased levels of the endosome marker Rab5 and co-localization of mammalian CKI with alphaSyn aggregates are observed in brain sections from alphaSyn-overexpressing mice and human synucleinopathies. Our results contribute to evidence that suggests alphaSyn-induced defects in endocytosis, exocytosis and/or recycling of vesicles involved in these cellular processes might contribute to the pathogenesis of synucleinopathies. |
