Department of Molecular Physiology and Pharmacology, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
J Biol Chem. 2012 Apr 13;287(16):13182-93. doi: 10.1074/jbc.M111.302612. Epub 2012 Feb 24.
Calpains are calcium-regulated cysteine proteases that have been implicated in the regulation of cell death pathways. Here, we used our calpain-1 null mouse model to evaluate the function of calpain-1 in neural degeneration following a rodent model of traumatic brain injury. In vivo, calpain-1 null mice show significantly less neural degeneration and apoptosis and a smaller contusion 3 days post-injury than wild type littermates. Protection from traumatic brain injury corroborated with the resistance of calpain-1 neurons to apoptosis induced by oxidative stress. Biochemical analysis revealed that caspase-3 activation, extracellular calcium entry, mitochondrial membrane permeability, and release of apoptosis-inducing factor from mitochondria are partially blocked in the calpain-1 null neurons. These findings suggest that the calpain-1 knock-out mice may serve as a useful model system for neuronal protection and apoptosis in traumatic brain injury and other neurodegenerative disorders in which oxidative stress plays a role.
钙蛋白酶是受钙离子调控的半胱氨酸蛋白酶，其在细胞死亡途径的调控中发挥作用。在这里，我们利用钙蛋白酶-1 基因敲除小鼠模型，评估钙蛋白酶-1在创伤性脑损伤的啮齿类动物模型中对神经退行性变的作用。在体内，钙蛋白酶-1 基因敲除小鼠在损伤后 3 天表现出明显较少的神经退行性变和细胞凋亡，挫伤也更小。创伤性脑损伤的保护作用与钙蛋白酶-1 神经元对氧化应激诱导的细胞凋亡的抵抗作用一致。生化分析显示，钙蛋白酶-1 缺失神经元中 caspase-3 的激活、细胞外钙离子内流、线粒体膜通透性以及凋亡诱导因子从线粒体中的释放部分受阻。这些发现表明，钙蛋白酶-1 基因敲除小鼠可能成为一个有用的模型系统，用于研究氧化应激在创伤性脑损伤和其他神经退行性疾病中发挥作用的神经元保护和细胞凋亡。
