Key Lab of Bioorganic Phosphorus Chemistry & Chemical Biology, Department of Chemistry , Tsinghua University , Beijing 100084 , P.R. China.
Beijing Institute for Brain Disorders, Beijing 100069 , P.R. China.
ACS Chem Neurosci. 2019 Feb 20;10(2):910-921. doi: 10.1021/acschemneuro.8b00447. Epub 2019 Jan 18.
Alpha-synuclein (α-syn), a small soluble protein containing 140 amino acids, is associated with the recycling pool of synaptic vesicles in presynaptic terminals. The misfolding and aggregation of α-syn is closely related to a group of neurodegenerative diseases, including Parkinson's disease (PD), which is one of the most common progressive neurodegenerative diseases. Varieties of the post-translational modifications (PTMs) of α-syn, including phosphorylation, ubiquitination, and glycosylation, have been detected in soluble and aggregated α-syn in vivo. These PTMs can have either positive or negative effects on α-syn aggregation and toxicity, which may play critical roles in PD pathogenesis. Herein, we review the advances in synthetic and semisynthetic chemistry to generate homogeneous α-syn variants with site-specific modifications. Using these modified α-syn, we gain insight into the consequences of PTMs on α-syn aggregation and other biophysical properties, which can help elucidate the role of PTMs in the pathogenesis of PD and develop potential therapies to PD.
α-突触核蛋白（α-syn），一种含有 140 个氨基酸的小可溶性蛋白，与突触前末梢中突触小泡的再循环池有关。α-syn 的错误折叠和聚集与包括帕金森病（PD）在内的一组神经退行性疾病密切相关，PD 是最常见的进行性神经退行性疾病之一。在体内可溶性和聚集的 α-syn 中已经检测到各种 α-syn 的翻译后修饰（PTMs），包括磷酸化、泛素化和糖基化。这些 PTMs 可能对 α-syn 的聚集和毒性有积极或消极的影响，这可能在 PD 的发病机制中起关键作用。本文综述了用于生成具有定点修饰的均一 α-syn 变体的合成和半合成化学的进展。使用这些修饰的 α-syn，我们深入了解 PTMs 对 α-syn 聚集和其他生物物理性质的影响，这有助于阐明 PTMs 在 PD 发病机制中的作用，并开发针对 PD 的潜在治疗方法。
