Nixon R A, Saito K I, Grynspan F, Griffin W R, Katayama S, Honda T, Mohan P S, Shea T B, Beermann M
Laboratories for Molecular Neuroscience, McLean Hospital, Belmont, Massachusetts 02178.
Ann N Y Acad Sci. 1994 Dec 15;747:77-91. doi: 10.1111/j.1749-6632.1994.tb44402.x.
Calpains (CANPs) are a family of calcium-dependent cysteine proteases under complex cellular regulation. By making selective limited proteolytic cleavages, they activate or alter the regulation of certain enzymes, including key protein kinases and phosphatases, and induce specific cytoskeletal rearrangements, accounting for their suspected involvement in intracellular signaling, vesicular trafficking, and structural stabilization. Calpain activity has been implicated in various aging phenomena, including cataract formation and erythrocyte senescence. Abnormal activation of the large stores of latent calpain in neurons induces cell injury and is believed to underlie neurodegeneration in excitotoxicity, Wallerian degeneration, and certain other neuropathologic states involving abnormal calcium influx. In Alzheimer's disease, we found the ratio of activated calpain I to its latent precursor isoform in neocortex to be threefold higher than that in normal individuals and those with Huntington's or Parkinson's disease. Immunoreactivity toward calpastatin, the endogenous inhibitor of calpain, was also markedly reduced in layers II-V of the neocortex in Alzheimer's disease. The excessive calpain system activation suggested by these findings represents a potential molecular basis for synaptic loss and neuronal cell death in the brain in Alzheimer's disease given the known destructive actions of calpain I and its preferential neuronal and synaptic localization. In surviving cells, persistent calpain activation may also contribute to neurofibrillary pathology and abnormal amyloid precursor protein trafficking/processing through its known actions on protein kinases and the membrane skeleton. The degree of abnormal calpain activation in the brain in Alzheimer's disease strongly correlated with the extent of decline in levels of secreted amyloid precursor protein in brain. Cytoskeletal proteins that are normally good calpain substrates become relatively calpain resistant when they are hyperphosphorylated, which may contribute to their accumulation in neurofibrillary tangles. As a major effector of calcium signals, calpain activity may mirror disturbances in calcium homeostasis and mediate important pathologic consequences of such disturbances.
钙蛋白酶（CANPs）是一类受复杂细胞调控的钙依赖性半胱氨酸蛋白酶。通过进行选择性有限的蛋白水解切割，它们激活或改变某些酶的调节，包括关键的蛋白激酶和磷酸酶，并诱导特定的细胞骨架重排，这解释了它们可能参与细胞内信号传导、囊泡运输和结构稳定的原因。钙蛋白酶活性与各种衰老现象有关，包括白内障形成和红细胞衰老。神经元中大量潜伏性钙蛋白酶的异常激活会导致细胞损伤，并且被认为是兴奋性毒性、沃勒变性以及其他某些涉及异常钙内流的神经病理状态下神经退行性变的基础。在阿尔茨海默病中，我们发现新皮质中激活的钙蛋白酶I与其潜伏前体异构体的比例比正常个体以及患有亨廷顿病或帕金森病的个体高三倍。在阿尔茨海默病患者的新皮质II-V层中，针对钙蛋白酶内源性抑制剂钙蛋白酶抑制蛋白的免疫反应性也明显降低。这些发现所表明的钙蛋白酶系统过度激活，鉴于钙蛋白酶I已知的破坏作用及其优先的神经元和突触定位，代表了阿尔茨海默病患者大脑中突触丧失和神经元细胞死亡的潜在分子基础。在存活细胞中，持续的钙蛋白酶激活也可能通过其对蛋白激酶和膜骨架的已知作用，导致神经原纤维病理改变以及淀粉样前体蛋白运输/加工异常。阿尔茨海默病患者大脑中钙蛋白酶异常激活的程度与大脑中分泌的淀粉样前体蛋白水平下降的程度密切相关。正常情况下是良好钙蛋白酶底物的细胞骨架蛋白在过度磷酸化时会变得相对抗钙蛋白酶，这可能有助于它们在神经原纤维缠结中的积累。作为钙信号的主要效应器，钙蛋白酶活性可能反映钙稳态的紊乱，并介导这种紊乱的重要病理后果。
