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。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的损伤导致神经元在重新进入细胞周期的尝试中失败，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一些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，但在神经退行性疾病模型中，一种名为OGG1的DNA修复蛋白可以保护神经元免于死亡。对培养神经元的研究表明，谷氨酸受体的激活可以诱导DNA的短暂损伤，由于钙介导的DNA修复蛋白APE1的上调，DNA损伤会迅速修复。此外，我们已经确定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钙稳态的机制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）在防止海马干细胞产生的神经元凋亡中的作用，这一发现表明有可能增加大脑替代丢失和受损神经元的能力。在其他研究中，我们发现新生成的神经元对DNA损伤诱导的凋亡高度敏感，因为它们的端粒酶和端粒相关蛋白TRF2水平较低。我们已经确定了Notch信号和一种名为Pancortin-2的新蛋白在中风神经元死亡中的作用。临床前研究表明，静脉注射免疫球蛋白和γ -分泌酶抑制剂对脑卒中模型有效。最近，我们已经证明神经元表达几种toll样受体，并提供证据表明，在阿尔茨海默病和中风的细胞培养和动物模型中，激活其中两种受体（TLR2和TLR4）可以触发细胞凋亡。在其他研究中，我们已经揭示了在衰老和神经退行性疾病的实验模型中，质膜氧化还原酶在保护神经元免受凋亡方面的重要作用。

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.