Apoptosis In Neurodegenerative Disorders

神经退行性疾病中的细胞凋亡

• 批准号: 7732197
• 负责人: MARK P MATTSON
• 金额: $ 118.57万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7732197
• 关键词: Alzheimer' s Disease; Animal Model; Apoptosis; Ataxia-Telangiectasia-Mutated protein kinase; Brain; Brain-Derived Neurotrophic Factor; Calcium; Cell Cycle; Cessation of life; Condition; Cultured Cells; DNA; DNA Damage; DNA repair protein; Diazoxide; Event; Experimental Models; Hippocampus (Brain); Homeostasis; Huntington Disease; Imaging technology; Intravenous Immunoglobulins; Investigation; Laboratories; Lead; Mitochondria; Mitochondrial DNA; Modeling; Molecular; Molecular Biology; Nerve Degeneration; Neurodegenerative Disorders; Neurological Models; Neurons; Neurosciences; OGG1 gene; Oxidative Stress; Parkinson Disease; Pathogenesis; Pharmaceutical Preparations; Potassium Channel; Process; Proteins; Proteomics; Role; Signal Transduction; Stem cells; Stroke; TLR4 gene; TP53 gene; Telomerase; Telomeric Repeat Binding Protein 2; Therapeutic Intervention; Toll-Like Receptor 2; Toll-like receptors; gamma secretase; inhibitor/antagonist; mitochondrial uncoupling protein; nervous system disorder; neuron apoptosis; notch protein; novel; novel therapeutics; pancortin 2; potassium ion; preclinical study; prevent; telomere

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. 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.

在神经退行性疾病中，例如阿尔茨海默氏症，帕金森氏症和亨廷顿疾病，神经元可能会因一种称为凋亡的程序性细胞死亡而死亡。 神经科学实验室的细胞和分子神经科学部分的主要努力旨在确定哪些触发神经退行性疾病中的凋亡以及如何通过在凋亡过程中靶向特定的分子事件来预防神经元变性。我们发现，一种称为p53的蛋白质参与了阿尔茨海默氏症，帕金森氏症和亨廷顿疾病的实验模型中的神经元死亡。 开发了p53的新型特异性抑制剂，并显示几种铅剂在中风和帕金森氏病动物模型中有效。 在其他研究中，我们确定了钾离子通量在中风模型中神经元变性的发病机理中的重要作用。 在中风模型中，一种称为二氮氧化物的药物，可打开线粒体钾通道。 在对神经元在阿尔茨海默氏病中死亡的机制的研究，我们发现对DNA的损害会导致神经元进行流产尝试重新进入细胞周期，从而激活ATM激酶和p53，p53引发凋亡。 我们对神经元中端粒功能的研究揭示了几种与端粒相关蛋白在预防凋亡中的作用。 线粒体DNA的损伤也可能引发凋亡，但是称为OGG1的DNA修复蛋白可以保护神经元免受神经退行性疾病模型的死亡。 此外，我们已经确定了一种线粒体解偶联蛋白（UCP4），该蛋白可以通过涉及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氏病有关的模型中的神经元。 我们还确定了脑衍生的神经营养因子（BDNF）在防止海马中由干细胞产生的神经元的凋亡中的作用，这一发现表明有可能增加大脑替代损失和受损神经元的能力。 在其他研究中，我们发现新近产生的神经元对DNA损伤诱导的凋亡高度敏感，因为它们的端粒酶水平较低和与端粒相关的蛋白TRF2。 我们已经确定了Notch信号传导的作用，并在中风中神经元死亡中称为pancortin-2的新型蛋白质。 临床前研究表明，静脉免疫球蛋白和γ-分泌酶抑制剂在中风模型中有效。 最近，我们表明神经元表达了几种类似Toll的受体，并提供了证据表明，这些受体中的两个（TLR2和TLR4）的激活可以触发阿尔茨海默氏病和中风的细胞培养和动物模型中的细胞凋亡。

项目成果

Viewpoint: mechanisms of action and therapeutic potential of neurohormetic phytochemicals.

• DOI: 10.2203/dose-response.07-004.mattson
• 发表时间: 2007-08-06
• 期刊: Dose-response : a publication of International Hormesis Society
• 作者: Mattson, Mark P;Son, Tae Gen;Camandola, Simonetta
• 通讯作者: Camandola, Simonetta

Neuroprotective actions of a histidine analogue in models of ischemic stroke.

组氨酸类似物在缺血性中风模型中的神经保护作用。

• DOI: 10.1111/j.1471-4159.2006.04412.x
• 发表时间: 2007
• 期刊: Journal of neurochemistry
• 影响因子: 4.7
• 作者: Tang,Sung-Chun;Arumugam,ThirumaV;Cutler,RoyG;Jo,Dong-Gyu;Magnus,Tim;Chan,SicL;Mughal,MohamedR;Telljohann,RichardS;Nassar,Matthew;Ouyang,Xin;Calderan,Andrea;Ruzza,Paolo;Guiotto,Andrea;Mattson,MarkP
• 通讯作者: Mattson,MarkP

Caspase-mediated suppression of glutamate (AMPA) receptor channel activity in hippocampal neurons in response to DNA damage promotes apoptosis and prevents necrosis: implications for neurological side effects of cancer therapy and neurodegenerative disord

Caspase 介导的海马神经元谷氨酸 (AMPA) 受体通道活性抑制，以响应 DNA 损伤，促进细胞凋亡并防止坏死：对癌症治疗和神经退行性疾病的神经副作用的影响

• DOI: 10.1006/nbdi.2000.0377
• 发表时间: 2001
• 期刊: Neurobiology of disease
• 影响因子: 6.1
• 作者: Lu,C;Fu,W;Mattson,MP
• 通讯作者: Mattson,MP

Neurodegeneration: nicked to death.

神经退行性变：被割伤致死。

• DOI: 10.1016/j.cub.2006.12.012
• 发表时间: 2007
• 期刊: Current biology : CB
• 作者: Wilson3rd,DavidM;Mattson,MarkP
• 通讯作者: Mattson,MarkP

Prophylactic activation of neuroprotective stress response pathways by dietary and behavioral manipulations.

• DOI: 10.1602/neurorx.1.1.111
• 发表时间: 2004-01-01
• 期刊: NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics
• 作者: Mattson, Mark P;Duan, Wenzhen;Guo, Zhihong
• 通讯作者: Guo, Zhihong