Department of Biochemistry, Molecular and Structural Biology, Jo ef Stefan Institute, Jamova 39, 1000 Ljubljana, Slovenia.
Curr Alzheimer Res. 2010 Feb;7(1):74-83. doi: 10.2174/156720510790274437.
The whole set of so-called >>conformational<< disorders, among them systemic amyloidoses, various dementias and other neurodegenerative diseases such as Parkinson's, Alzheimer's and amyotropic lateral sclerosis, may have similar molecular backgrounds: changes in protein conformation and aggregation lead to toxic amyloid oligomers and fibrils. The so called aggresomes in eukaryotes (equivalent to inclusion bodies in prokaryotes), located at the centriole by the nucleus and composed of aggregated proteins, are believed to sequester the toxic material. They eventually get cleared from the cell by autophagy. When the cell defence system fails due to continuous production of a mutated protein or to other damage to the cell such as oxidative stress or protein modification as part of normal aging, familial or sporadic neurodegenerative diseases develop. Initially - for years - they are silent with no or mild symptoms. It could well be that aggregates represent a response to some other trigger or even a means of defence. However, the inherited cases with mutations leading to increased aggregation suggest the opposite to be the case. Evidence has accumulated that the soluble oligomers of amyloidogenic proteins are themselves cytotoxic and trigger a cascade of detrimental events in the cell, as summarized in the "amyloid cascade hypothesis". Among other plausible hypotheses for the mechanism of toxicity is the "channel hypothesis", which states that the soluble oligomers interact with cell membranes, causing influx of Ca2+ ions, which is an early sign of pathology and contributes to uncontrolled neurotransmission. Another factor are metal ions, such as Zn(2+), Cu(2+), Fe(3+), Al(3+), etc., leading to the "metal hypothesis". The delicate balance of metal ions in the brain is important to prevent oxidative stress, which can itself modify proteins and make them aggregation-prone. The advances in molecular and cellular studies will hopefully lead to novel therapies and eventually to a cure.
整套所谓的“构象”疾病，包括系统性淀粉样变性、各种痴呆和其他神经退行性疾病，如帕金森病、阿尔茨海默病和肌萎缩性侧索硬化症，可能具有相似的分子基础：蛋白质构象和聚集的变化导致毒性淀粉样寡聚体和纤维。真核生物中的所谓聚集物（相当于原核生物中的包含体）位于核旁的中心粒，由聚集的蛋白质组成，被认为可以隔离毒性物质。它们最终通过自噬从细胞中清除。当由于持续产生突变蛋白或由于其他细胞损伤（如氧化应激或作为正常衰老一部分的蛋白质修饰）导致细胞防御系统失效时，家族性或散发性神经退行性疾病就会发展。最初——多年来——它们是沉默的，没有或只有轻微的症状。很可能聚集物代表了对其他一些触发因素的反应，甚至是一种防御手段。然而，导致聚集增加的遗传病例表明情况恰恰相反。越来越多的证据表明，淀粉样蛋白原性蛋白的可溶性寡聚体本身就具有细胞毒性，并在细胞中引发一系列有害事件，这在“淀粉样蛋白级联假说”中有所总结。毒性机制的其他合理假说包括“通道假说”，该假说指出可溶性寡聚体与细胞膜相互作用，导致 Ca2+离子内流，这是病理学的早期迹象，并导致不受控制的神经传递。另一个因素是金属离子，如 Zn(2+)、Cu(2+)、Fe(3+)、Al(3+)等，导致“金属假说”。大脑中金属离子的微妙平衡对于防止氧化应激很重要，氧化应激本身可以修饰蛋白质并使它们易于聚集。分子和细胞研究的进展有望带来新的治疗方法，并最终治愈疾病。
