Department of Pharmacology, University of Pennsylvania School of Medicine, 3620 Hamilton Walk, 125 John Morgan Building, Philadelphia, PA 19104-6084, USA.
Biochem Biophys Res Commun. 2010 Jan 15;391(3):1415-20. doi: 10.1016/j.bbrc.2009.12.079. Epub 2009 Dec 21.
Alpha-synuclein (alpha-syn) amyloid filaments are the major ultrastructural component of pathological inclusions that define several neurodegenerative disorders, including Parkinson disease and other disorders that are collectively termed synucleinopathies. Since the aggregation of alpha-syn is associated with the etiology of these diseases, defining the molecular elements that influence this process may have important therapeutics implication. The deletions of major portions of the hydrophobic region of alpha-syn (Delta74-79 and Delta71-82) impair the ability to form amyloid. However, mutating residue E83 to an A restored the ability of these proteins to form amyloid. Additionally supporting an inhibitory role of residue E83 on amyloid formation, mutating this residue to an A enhanced amyloid formation in the presence of small molecule inhibitors, such as dopamine and EGCG. Our data, therefore, suggest that the presence and placement of the highly charged E83 residue plays a significant inhibitory role in alpha-syn amyloid formation and these findings provide important insights in the planning of therapeutic agents that may be capable of preventing alpha-syn amyloid formation.
α-突触核蛋白（α-syn）淀粉样纤维是定义几种神经退行性疾病（包括帕金森病和其他统称为突触核蛋白病的疾病）的病理性包涵体的主要超微结构成分。由于 α-syn 的聚集与这些疾病的病因有关，因此确定影响该过程的分子因素可能具有重要的治疗意义。α-syn 疏水区域的主要部分（Δ74-79 和 Δ71-82）缺失会损害形成淀粉样纤维的能力。然而，将残基 E83 突变为 A 恢复了这些蛋白质形成淀粉样纤维的能力。此外，残基 E83 对淀粉样纤维形成的抑制作用，突变该残基为 A 在小分子抑制剂（如多巴胺和 EGCG）存在下增强了淀粉样纤维的形成。因此，我们的数据表明，带正电荷的 E83 残基的存在和位置在 α-syn 淀粉样纤维形成中起着重要的抑制作用，这些发现为可能能够预防 α-syn 淀粉样纤维形成的治疗剂的规划提供了重要的见解。
