SELECTIVE VULNERABILITY OF SPORADIC NEURODEGENERATIVE DISEASE

神经退行性疾病-肌萎缩侧索硬化症， 帕金森氏症和阿尔茨海默氏症--在临床上是毁灭性的 导致选择性神经元损伤和死亡的紊乱。我们的将军 假说是细胞内钙增加，而钙有限 缓冲能力在神经变性细胞中可能是至关重要的 受伤。我们在肌萎缩侧索硬化症中的具体研究记录了 抗电压门控钙通道(VGCC)抗体，导致 在体外增加细胞内钙离子和细胞毒性；我们的研究 在阿尔茨海默病中发现了β-淀粉样多肽 增加细胞内钙，尽管是通过不同的机制，导致 对体外细胞毒性的影响。肌萎缩侧索硬化症免疫球蛋白增强不同细胞的钙电流 神经元性VGCC(如浦肯野细胞和脂质双层中的P型通道； 表达大鼠脑VGCC的非洲爪哇卵母细胞中的N型通道和P型OR 运动神经元细胞系中的Q型通道[VSC 4.1])。在VSC 4.1中， 肌萎缩侧索硬化症免疫球蛋白介导的钙电流增加 细胞内钙离子与细胞死亡有关。这个细胞系统以及 注射了VGCC和大鼠脑mRNA的非洲爪哇卵母细胞将允许我们使用 钙成像和电生理技术表征 肌萎缩侧索硬化症免疫球蛋白对不同VGCC及钙稳态和TO的影响 研究第二信使系统对细胞毒性的贡献， 包括G蛋白、蛋白激酶和磷酸酶，以及钙 结合蛋白Calbindin D28K和小白蛋白。 影响散发性阿尔茨海默病选择性易感性的因素 没有很好地定义。我们最近的研究证明，β淀粉样蛋白导致 导致黑质细胞内钙离子升高和细胞死亡 细胞系。细胞外钙的去除减弱了细胞毒性，但 VGCC拮抗剂不起作用。金精羧酸，一种抗癌药物 细胞凋亡，完全阻止细胞死亡。这个细胞系统将允许我们 使用相同的钙成像、电生理和 确定β淀粉样蛋白如何导致高血压的药理学技术 细胞内钙，并确定细胞内钙升高的作用 钙在介导β-淀粉样蛋白诱导的细胞毒性中的作用及钙离子的影响 钙结合蛋白、钙结合蛋白D28K和/或小白蛋白对细胞损伤的影响。 这样的研究应该让我们深入了解增加 细胞内钙及选择性神经元钙缓冲的改变 散发性神经退行性疾病的脆弱性。

The neurodegenerative diseases - Amyotrophic Lateral Sclerosis (ALS), Parkinson's disease, and Alzheimer's disease - are devastating clinical disorders that result in selective neuronal injury and death. Our general hypothesis is that increased intracellular calcium, and limited calcium buffering capacity, may be critically important in neurodegenerative cell injury. Our specific studies in ALS have documented the presence of antibodies to voltage-gated calcium channels (VGCC), which lead to increased intracellular calcium and cytotoxicity in vitro; and our studies in Alzheimer's disease have documented that beta amyloid peptide also increases intracellular calcium, albeit by a different mechanism, leading to cytoxicity in vitro. ALS IgG enhance calcium current of different neuronal VGCC (e.g. P-type channels in Purkinje cells and lipid bilayers; N-type channels in Xenopus oocytes expressing rat brain VGCC; and P-type or Q-type channels in a motor neuron cell line [VSC 4.1]). In VSC 4.1, the ALS IgG-mediated increase in calcium current leads to increased intracellular calcium and to cell death. This cell system as well as Xenopus oocytes injected with VGCC and rat brain mRNA will allow us to use calcium imaging and electrophysiological techniques to characterize the effects of ALS IgG on different VGCC and on calcium homeostasis and to examine the contribution to cytotoxicity of second messenger systems, including G proteins, protein kinases and phosphatases, and the calcium binding proteins calbindin D28K and parvalbumin. Factors mediating selective vulnerability in sporadic Alzheimer's disease are not well defined. Our recent studies document that beta amyloid leads to increased intracellular calcium and cell death of a substantia nigra cell line. Removal of extracellular calcium attenuates cytotoxicity, but VGCC antagonists have not effect. Aurintricarboxylic acid, an inhibitor of apoptosis, completely blocks cell death. This cell system will permit us to employ the same calcium imaging, electrophysiological and pharmacological techniques to define how beta amyloid leads to increased intracellular calcium, and to determine the role of increased intracellular calcium in mediating beta amyloid-induced cytoxicity and the influence of calcium binding proteins, calbindin D28K and/or parvalbumin on cell injury. Such studies should provide insight into the roles played by increasing intracellular calcium and altered calcium buffering on selective neuronal vulnerability in sporadic neurodegenerative disorders.