Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158, USA.
Hum Mol Genet. 2012 Jun 1;21(11):2432-49. doi: 10.1093/hmg/dds058. Epub 2012 Feb 21.
The aggregation of α-synuclein (αSyn) is a neuropathologic hallmark of Parkinson's disease and other synucleinopathies. In Lewy bodies, αSyn is extensively phosphorylated, predominantly at serine 129 (S129). Recent studies in yeast have shown that, at toxic levels, αSyn disrupts Rab homeostasis, causing an initial endoplasmic reticulum-to-Golgi block that precedes a generalized trafficking collapse. However, whether αSyn phosphorylation modulates trafficking defects has not been evaluated. Here, we show that constitutive expression of αSyn in yeast impairs late-exocytic, early-endocytic and/or recycling trafficking. Although members of the casein kinase I (CKI) family phosphorylate αSyn at S129, they attenuate αSyn toxicity and trafficking defects by an S129 phosphorylation-independent mechanism. Surprisingly, phosphorylation of S129 modulates αSyn 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 αSyn aggregates are observed in brain sections from αSyn-overexpressing mice and human synucleinopathies. Our results contribute to evidence that suggests αSyn-induced defects in endocytosis, exocytosis and/or recycling of vesicles involved in these cellular processes might contribute to the pathogenesis of synucleinopathies.
α-突触核蛋白（αSyn）的聚集是帕金森病和其他突触核蛋白病的神经病理学标志。在路易小体中，αSyn 广泛磷酸化，主要在丝氨酸 129 位（S129）。最近在酵母中的研究表明，在毒性水平下，αSyn 会破坏 Rab 平衡，导致内质网到高尔基体的初始阻断，随后是广泛的运输崩溃。然而，αSyn 磷酸化是否调节运输缺陷尚未得到评估。在这里，我们表明酵母中 αSyn 的组成型表达会损害晚期胞吐、早期内吞和/或再循环运输。尽管酪蛋白激酶 I（CKI）家族的成员在 S129 位磷酸化 αSyn，但它们通过 S129 磷酸化非依赖性机制减轻 αSyn 的毒性和运输缺陷。令人惊讶的是，S129 磷酸化以严格受遗传背景决定的方式调节 αSyn 的毒性和运输缺陷。在αSyn 过表达小鼠和人类突触核蛋白病的脑组织切片中观察到内体形态异常、内体标记物 Rab5 水平升高以及哺乳动物 CKI 与 αSyn 聚集体的共定位。我们的结果有助于证明，涉及这些细胞过程的内吞作用、胞吐作用和/或囊泡再循环的 αSyn 诱导缺陷可能导致突触核蛋白病的发病机制。
