Luibl Volker, Isas Jose M, Kayed Rakez, Glabe Charles G, Langen Ralf, Chen Jeannie
Beckman Macular Research Center, Doheny Eye Institute and Zilkha Neurogenetic Institute, University of Southern California Keck School of Medicine, Los Angeles, California 90033, USA.
J Clin Invest. 2006 Feb;116(2):378-85. doi: 10.1172/JCI25843.
Protein misfolding and aggregation are thought to underlie the pathogenesis of many amyloid diseases, such as Alzheimer and Parkinson diseases, whereby a stepwise protein misfolding process begins with the conversion of soluble protein monomers to prefibrillar oligomers and progresses to the formation of insoluble amyloid fibrils. Drusen are extracellular deposits found in aging eyes and in eyes afflicted with age-related macular degeneration (AMD). Recent characterizations of drusen have revealed protein components that are shared with amyloid deposits. However, characteristic amyloid fibrils have thus far not been identified in drusen. In this study, we tested the hypothesis that nonfibrillar oligomers may be a common link in amyloid diseases. Oligomers consisting of distinct amyloidogenic proteins and peptides can be detected by a recently developed antibody that is thought to recognize a common structure. Notably, oligomers exhibit cellular toxicity, which suggests that they play a role in the pathogenesis of neurodegenerative diseases. Through use of the anti-oligomer antibody, we came to observe the presence of nonfibrillar, toxic oligomers in drusen. Conversely, no reactivity was observed in age-matched control eyes without drusen. These results suggest that amyloid oligomers may be involved in drusen biogenesis and that similar protein misfolding processes may occur in AMD and amyloid diseases.
蛋白质错误折叠和聚集被认为是许多淀粉样疾病发病机制的基础，如阿尔茨海默病和帕金森病，在这些疾病中，蛋白质逐步错误折叠过程始于可溶性蛋白质单体转化为前纤维寡聚体，并进展为不溶性淀粉样纤维的形成。玻璃膜疣是在衰老眼睛和患有年龄相关性黄斑变性（AMD）的眼睛中发现的细胞外沉积物。最近对玻璃膜疣的特征描述揭示了与淀粉样沉积物共有的蛋白质成分。然而，迄今为止在玻璃膜疣中尚未鉴定出特征性淀粉样纤维。在本研究中，我们检验了非纤维状寡聚体可能是淀粉样疾病共同环节的假说。由不同的淀粉样蛋白和肽组成的寡聚体可以通过一种最近开发的抗体检测到，该抗体被认为能识别一种共同结构。值得注意的是，寡聚体表现出细胞毒性，这表明它们在神经退行性疾病的发病机制中起作用。通过使用抗寡聚体抗体，我们观察到玻璃膜疣中存在非纤维状、有毒性的寡聚体。相反，在没有玻璃膜疣的年龄匹配对照眼中未观察到反应性。这些结果表明淀粉样寡聚体可能参与玻璃膜疣的生物发生，并且在AMD和淀粉样疾病中可能发生类似的蛋白质错误折叠过程。
