Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4.
Trends Neurosci. 2011 Dec;34(12):646-56. doi: 10.1016/j.tins.2011.09.001. Epub 2011 Oct 22.
Caspases are cysteine-aspartic proteases that post-translationally modify their substrates through cleavage at specific sites, which causes either substrate inactivation or a gain of function through the generation of active fragments. Currently, each caspase is categorized as either an initiator of apoptosis or an end-stage executioner. Caspase-6 was originally identified as an executioner caspase owing to its role in cleavage of nuclear lamins. However, it has since been shown that caspase-6 cleaves caspases-2, 3 and 8. Furthermore, active caspase-6 is present in post mortem brains of Huntington and Alzheimer disease subjects that do not yet display apoptotic morphology, which suggests a function distinct from its well-validated executioner role. In this review, we discuss evidence to date regarding the role of caspase-6 in neurodegeneration. The findings suggest that selective inhibitors of caspase-6 may have therapeutic potential for various neurodegenerative disorders.
半胱天冬氨酸蛋白酶是一类在翻译后通过特定位点的切割来修饰其底物的蛋白水解酶，这种切割会导致底物失活或通过生成活性片段获得功能。目前，每种半胱天冬氨酸蛋白酶都被归类为凋亡的起始因子或终末执行者。半胱天冬氨酸蛋白酶-6 最初被确定为执行者半胱天冬氨酸蛋白酶，因为它在核纤层蛋白切割中的作用。然而，此后的研究表明，半胱天冬氨酸蛋白酶-6 可以切割半胱天冬氨酸蛋白酶-2、3 和 8。此外，在没有表现出凋亡形态的亨廷顿病和阿尔茨海默病患者的死后大脑中存在活性半胱天冬氨酸蛋白酶-6，这表明它具有与其经过充分验证的执行者作用不同的功能。在这篇综述中，我们讨论了迄今为止关于半胱天冬氨酸蛋白酶-6 在神经退行性变中的作用的证据。研究结果表明，半胱天冬氨酸蛋白酶-6 的选择性抑制剂可能对各种神经退行性疾病具有治疗潜力。
