el-Agnaf O M A, Irvine G B
Department of Biological Sciences, Lancaster University, Lancaster LA1 4YQ, UK.
Biochem Soc Trans. 2002 Aug;30(4):559-65. doi: 10.1042/bst0300559.
Fibrillar deposits of alpha-synuclein occur in several neurodegenerative diseases. Two mutant forms of alpha-synuclein have been associated with early-onset Parkinson's disease, and a fragment has been identified as the non-amyloid-beta peptide component of Alzheimer's disease amyloid (NAC). Upon aging, solutions of alpha-synuclein and NAC change conformation to beta-sheet, detectable by CD spectroscopy, and form oligomers that deposit as amyloid-like fibrils, detectable by electron microscopy. These aged peptides are also neurotoxic. Experiments on fragments of NAC have enabled the region of NAC responsible for its aggregation and toxicity to be identified. NAC(8-18) is the smallest fragment that aggregates, as indicated by the concentration of peptide remaining in solution after 3 days, and forms fibrils, as determined by electron microscopy. Fragments NAC(8-18) and NAC(8-16) are toxic, whereas NAC(12-18), NAC(9-16) and NAC(8-15) are not. Hence residues 8-16 of NAC comprise the region crucial for toxicity. Toxicity induced by alpha-synuclein, NAC and NAC(1-18) oligomers occurs via an apoptotic mechanism, possibly initiated by oxidative damage, since these peptides liberate hydroxyl radicals in the presence of iron. Molecules with anti-aggregational and/or antioxidant properties may therefore be potential therapeutic agents.
α-突触核蛋白的纤维状沉积物出现在多种神经退行性疾病中。α-突触核蛋白的两种突变形式与早发性帕金森病有关，并且一个片段已被鉴定为阿尔茨海默病淀粉样蛋白（NAC）的非淀粉样β肽成分。随着年龄增长，α-突触核蛋白和NAC的溶液会转变为β折叠构象，可通过圆二色光谱法检测到，并且会形成寡聚体，这些寡聚体会沉积为淀粉样纤维，可通过电子显微镜检测到。这些老化的肽也具有神经毒性。对NAC片段的实验使得能够鉴定出NAC中负责其聚集和毒性的区域。NAC(8 - 18)是聚集的最小片段，这由3天后溶液中剩余的肽浓度表明，并且通过电子显微镜确定其形成了纤维。片段NAC(8 - 18)和NAC(8 - 16)具有毒性，而NAC(12 - 18)、NAC(9 - 16)和NAC(8 - 15)则没有毒性。因此，NAC的8 - 16位残基构成了毒性的关键区域。由α-突触核蛋白、NAC和NAC(1 - 18)寡聚体诱导的毒性通过凋亡机制发生，可能由氧化损伤引发，因为这些肽在铁存在的情况下会释放羟基自由基。因此，具有抗聚集和/或抗氧化特性的分子可能是潜在的治疗剂。
