Apoptosis In Neurodegenerative Disorders

在阿尔茨海默病、帕金森病和亨廷顿病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分的一项主要工作旨在确定在神经退行性疾病中触发细胞凋亡的原因，以及如何通过靶向细胞凋亡过程中的特定分子事件来预防神经元变性。我们发现一种叫做p53的蛋白质参与了阿尔茨海默病、帕金森病和亨廷顿病实验模型中神经元的死亡。新的特异性p53抑制剂被开发出来，一些先导药物在中风和帕金森病的动物模型中显示有效。在其他研究中，我们确定了钾离子通量在脑卒中模型神经元变性发病机制中的重要作用。在中风模型中，一种叫做二氮氧化物的药物可以打开线粒体钾通道，对神经元有保护作用。

In neurodegenerative disorders such as Alzheimers, Parkinsons and Huntingtons 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 Alzheimers, Parkinsons and Huntingtons diseases. Novel specific inhibitors of p53 were developed and several lead agents were shown to be effective in animal models of stroke and Parkinsons 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 Alzheimers 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. Studies of cultured neurons demonstrated that activation of glutamate receptors can induce a transient damage to DNA which is rapidly repaired as the result of calcium-mediated upregulation of the DNA repair protein APE1. In addition, we have identified a mitochondrial uncoupling protein (UCP4) that can protect neurons in models relevant to stroke and Alzheimers 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. In other studies we have found that newly generated neurons are highly sensitive to DNA damage-induced apoptosis because they have low levels of telomerase and the telomere-associated protein TRF2. We have established roles for Notch signaling and a novel protein called Pancortin-2 in neuronal death in stroke. Preclinical studies have shown that intravenous immunoglobulin and gamma-secretase inhibotors are effective in stroke models. More recently, we have shown that neurons express several toll-like receptors, and have provided evidence that activation of two of these receptors (TLR2 and TLR4) can trigger apoptosis in cell culture and animal models of Alzheimer's disease and stroke. In other studies we have revealed important roles for plasma membrane redox enzymes in protecting neurons against apoptosis in experimental models of aging and neurodegenerative disorders. Two novel mechanisms of protecting neurons against apoptosis in experimental models of stroke and Alzheimer's disease have been discovered. First, we found that the plasma membrane redox enzymes, including NQO1 can protect neurons against amyloid toxicity. Second, we found that the calcium channel inhibitor pregabalin can protect neurons against apoptosis in cell cutlure and animal models of stroke. These findings suggest novel approaches for improving the outcome of a stroke or suppressing the AD process.