Apoptosis In Neurodegenerative Disorders

在神经退行性疾病如阿尔茨海默病、帕金森病和亨廷顿病中，神经元可能通过称为细胞凋亡的程序性细胞死亡形式死亡。 神经科学实验室的细胞和分子神经科学部分的一项主要工作旨在确定是什么触发了神经退行性疾病的细胞凋亡，以及如何通过靶向细胞凋亡过程中的特定分子事件来预防神经元变性。我们发现，一种名为p53的蛋白质与阿尔茨海默病、帕金森病和亨廷顿病的实验模型中的神经元死亡有关。 新型p53特异性抑制剂被开发出来，几种先导药物在中风和帕金森病的动物模型中显示出有效性。 在其他研究中，我们建立了重要的作用，钾离子流的发病机制中的神经元变性的中风模型。 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。 在阿尔茨海默病中神经元死亡机制的研究中，我们发现DNA损伤导致神经元重新进入细胞周期的尝试失败，导致ATM激酶和p53激活，从而触发细胞凋亡。 我们对神经元中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OGG 1的DNA修复蛋白可以保护神经元免于神经退行性疾病模型中的死亡。 此外，我们已经确定了一种线粒体解偶联蛋白（UCP 4），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中风和阿尔茨海默病相关模型中的神经元。 我们还确定了脑源性神经营养因子（BDNF）在防止海马体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，我们发现新产生的神经元对DNA损伤诱导的凋亡高度敏感，因为它们具有低水平的端粒酶和端粒相关蛋白TRF 2。 最近，我们确定了Notch信号传导和一种名为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分泌酶抑制剂对中风模型有效。

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. 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. More recently, we 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.