Proteomic Unit, Centre for Psychiatric Neuroscience, Department of Psychiatry, CHUV, CERY, Prilly-Lausanne, CH-1008, Switzerland.
Exp Biol Med (Maywood). 2013 May;238(5):519-24. doi: 10.1177/1535370213488484.
It is widely accepted that protein oxidation is involved in a variety of diseases, including neurodegenerative diseases. Especially during aging, a reduction in anti-oxidant defence mechanisms leads to an increased formation of free radical oxygen species and consequently results in a damage of proteins, including mitochondrial and synaptic ones. Even those proteins involved in repair and protein clearance via the ubiquitin proteasome and lysosomal system are subject to damage and show a reduced function. Here, we will discuss a variety of mechanisms and provide examples where cognition is affected and where repair mechanisms are no longer sufficient to compensate for a dysfunction of damaged proteins or even may become toxic. Next to physiological deficits, an accumulation of deficient proteins in aggresomes may occur and result in a formation of pathological hallmark structures typical for aging and disease. A major challenge is how to prevent aberrant oxidation, given that oxidation plays an essential role in aging and neurodegenerative diseases. Particularly interesting are the possibilities to reduce the formation of radical oxygen species leading to a dysfunction of protein repair and protein clearance, or to a formation of toxic byproducts accelerating neurodegeneration.
普遍认为，蛋白质氧化参与了多种疾病，包括神经退行性疾病。特别是在衰老过程中，抗氧化防御机制的减少会导致自由基氧物种的形成增加，从而导致蛋白质（包括线粒体和突触蛋白）受损。甚至那些通过泛素蛋白酶体和溶酶体系统参与修复和蛋白质清除的蛋白质也会受到损伤，功能降低。在这里，我们将讨论各种机制，并提供认知受到影响的例子，以及修复机制不再足以补偿受损蛋白质的功能障碍，甚至可能变得有毒的例子。除了生理缺陷外，聚集物中缺陷蛋白的积累也可能导致衰老和疾病特有的病理性标志性结构的形成。一个主要的挑战是如何防止异常氧化，因为氧化在衰老和神经退行性疾病中起着至关重要的作用。特别有趣的是减少自由基氧物种形成的可能性，这可能导致蛋白质修复和蛋白质清除功能障碍，或者形成加速神经退行性变的有毒副产物。
