氧化应激包括DNA损伤,增加脂质和蛋白质氧化,是衰老和神经变性的重要特征,表明内源性抗氧化剂保护途径不足或不堪重负。重要的是,氧化蛋白质损伤导致功能失调的线粒体或蛋白质聚集体的年龄依赖性积累。此外,环境毒素,如鱼藤酮和百草枯,是神经退行性疾病发病的危险因素,也促进蛋白质氧化。已在动物模型中测试了补充旨在抑制氧化应激引发的主要抗氧化剂系统的明显方法,并获得了阳性结果。然而,这些发现尚未有效地转化为治疗人类患者,和使用自由基清除分子如α-生育酚的抗氧化疗法的临床试验,抗坏血酸和辅酶Q取得了有限的成功,强调了这种方法的几个局限性。这些可能包括:(1)自由基清除抗氧化剂不能逆转对蛋白质和细胞器的既定损害;(2)自由基清除抗氧化剂是氧化剂特异性的,并且只有在神经变性的特定机制涉及它们所靶向的反应性物种时才能有效,并且(3)由于反应性物种在生理信号传导中起着重要作用,抑制内源性氧化剂可能有害。因此,需要可以规避这些限制的替代方法。虽然以前没有被认为是抗氧化系统,但我们认为自噬-溶酶体活性,通过去除受损或功能失调的蛋白质和细胞器,可以在神经退行性疾病中发挥这种基本功能。
Oxidative stress including DNA damage, increased lipid and protein oxidation, are important features of aging and neurodegeneration suggesting that endogenous antioxidant protective pathways are inadequate or overwhelmed. Importantly, oxidative protein damage contributes to age-dependent accumulation of dysfunctional mitochondria or protein aggregates. In addition, environmental toxins such as rotenone and paraquat, which are risk factors for the pathogenesis of neurodegenerative diseases, also promote protein oxidation. The obvious approach of supplementing the primary antioxidant systems designed to suppress the initiation of oxidative stress has been tested in animal models and positive results were obtained. However, these findings have not been effectively translated to treating human patients, and clinical trials for antioxidant therapies using radical scavenging molecules such as α-tocopherol, ascorbate and coenzyme Q have met with limited success, highlighting several limitations to this approach. These could include: (1) radical scavenging antioxidants cannot reverse established damage to proteins and organelles; (2) radical scavenging antioxidants are oxidant specific, and can only be effective if the specific mechanism for neurodegeneration involves the reactive species to which they are targeted and (3) since reactive species play an important role in physiological signaling, suppression of endogenous oxidants maybe deleterious. Therefore, alternative approaches that can circumvent these limitations are needed. While not previously considered an antioxidant system we propose that the autophagy-lysosomal activities, may serve this essential function in neurodegenerative diseases by removing damaged or dysfunctional proteins and organelles.