Apoptosis In Neurodegenerative Disorders

在阿尔茨海默氏症、帕金森氏症和亨廷顿氏症等神经退行性疾病中，神经元可能会因一种称为细胞凋亡的程序性细胞死亡而死亡。神经科学实验室细胞和分子神经科学部门的一项主要工作旨在确定是什么触发了神经退行性疾病中的细胞凋亡，以及如何通过靶向细胞凋亡过程中的特定分子事件来防止神经元变性。我们发现，在阿尔茨海默氏症、帕金森氏病和亨廷顿病的实验模型中，一种名为p53的蛋白质参与了神经元的死亡。开发了新的P53特异性抑制剂，几种先导剂在中风和帕金森病的动物模型中被证明是有效的。在其他研究中，我们确定了钾离子通量在卒中模型神经元变性发病机制中的重要作用。一种名为二氮嗪的药物可以打开线粒体钾通道，在中风模型中具有神经保护作用。在对阿尔茨海默病中神经元死亡机制的研究中，我们发现DNA的损伤会导致神经元重新进入细胞周期的尝试流产，导致ATM激酶和P53的激活，从而引发细胞凋亡。我们对神经元端粒功能的研究揭示了几种端粒相关蛋白在防止细胞凋亡中的作用。线粒体DNA的损伤也可能引发细胞凋亡，但一种名为OGG1的DNA修复蛋白可以保护神经退行性疾病模型中的神经元免于死亡。此外，我们还发现了一种线粒体解偶联蛋白(UCP4)，它可以通过抑制氧化应激和稳定细胞内钙稳态来保护与中风和阿尔茨海默病相关的模型中的神经元。我们还确定了脑源性神经营养因子(BDNF)在防止海马区干细胞产生的神经元凋亡方面的作用，这一发现表明，有可能增加大脑的能力，以取代丢失和受损的神经元。

In neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's diseases, neurons may die by a form of programmed cell death called apoptosis. A major effort in the Cellular and Molecular Neurosciences section of the Laboratory of Neurosciences is aimed at establishing what triggers apoptosis in neurodegenerative disorders and how neuronal degeneration might be prevented by targeting specific molecular events in the process of apoptosis. We have found that a protein called p53 is involved in the death of neurons in experimental models of Alzheimer's, Parkinson's and Huntington's diseases. Novel specific inhibitors of p53 were developed and several lead agents were shown to be effective in animal models of stroke and Parkinson's disease. In other studies we established important roles for potassium ion fluxes in the pathogenesis of neuronal degeneration in models of stroke. A drug called diazoxide that opens mitochondrial potassium channels was neuronprotective in models of stroke. In studies of the mechanism by which neurons die in Alzheimer's disease we have found that damage to DNA causes the neurons to undergo an abortive attempt to re-enter the cell cycle resulting in activation of the ATM kinase and p53 which trigger apoptosis. Our studies of telomere function in neurons have revealed roles for several telomere-associated proteins in preventing apoptosis. Damage to mitochondrial DNA may also trigger apoptosis, but a DNA repair protein called OGG1 can protect neurons from dying in models of neurodegenerative disorders. In addition, we have identified a mitochondrial uncoupling protein (UCP4) that can protect neurons in models relevant to stroke and Alzheimer's disease by a mechanism involving suppression of oxidative stress and stabilization of cellular calcium homeostasis. We have also established roles for brain-derived neurotrophic factor (BDNF) in preventing the apoptosis of neurons produced from stem cells in the hippocampus, a finding that suggests the possibility of increasing the capacity of the brain to replace lost and damaged neurons.