APO E Receptors and Modulation of Fast Axonal Transport

APO E 受体和快速轴突运输的调节

• 批准号: 6623050
• 负责人: Joachim J Herz
• 金额: $ 37.05万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-15 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6623050
• 关键词: apolipoprotein E; axon; dynein ATPase; enzyme activity; gene targeting; genetically modified animals; intracellular transport; kinesin; laboratory mouse; mutant; neuronal transport; protein transport; receptor; synapses

DESCRIPTION (provided by applicant): Members of the low-density-lipoprotein (LDL) receptor gene family have recently been found to participate in signal transduction pathways during the development of the brain. Reelin, a large secreted protein that bears no resemblance to lipoproteins and is not involved in lipid transport, binds to the extracellular domains of two members of this gene family, termed VLDL receptor (VLDLR) and ApoE receptor 2 (ApoER2). Binding of this ligand activates a cytoplasmic signaling cascade that apparently involves tyrosine kinases as well as the serine/threonine kinases Cdk5 and GSK-3beta. Disruption of this pathway results in abnormal phosphorylation of the microtubule-associated protein tau and therefore is likely to impair axonal transport processes, which are dependent on the normal function of microtubules. ApoER2 and VLDLR both are expressed abundantly on the surface of embryonic neurons as well as on neurons in the mature brain, where they can also function as receptors for Apolipoprotein E (ApoE). ApoE exists in three major isoforms. One of these isoforms, ApoE4 is genetically associated with late-onset Alzheimer disease. The biochemical basis by which ApoE4 predisposes its carriers to late-onset Alzheimer disease is poorly understood. We hypothesize that ApoE4 acts as a competitor for signaling molecules such as Reelin and reduces their binding to the receptors on the neuronal surface, thereby impairing physiological signaling pathways that regulate neuronal transport and synaptic protein transport. This model would provide a mechanistic basis on which the loss of synapses, which correlates with dementia and precedes the formation of plaques and neurofibrillary tangles, could be explained. The goal of the current proposal is to elucidate the cytoplasmic signaling pathways that are activated by the binding of Reelin to its receptors on the neuronal cell surface and to study the effect of Reelin on axonal transport, the activity of molecular motors such as dynein and kinesin, and the transport of synaptic proteins to their target sites.

描述（由申请人提供）： 低密度脂蛋白（LDL）受体基因家族的成员最近具有 发现在 大脑的发展。 reelin，一种大的分泌蛋白，不带 与脂蛋白相似，不参与脂质转运，与 该基因家族两个成员的细胞外域称为VLDL 受体（VLDLR）和APOE受体2（apoer2）。该配体的结合激活 显然涉及酪氨酸激酶的细胞质信号级联 以及丝氨酸/苏氨酸激酶CDK5和GSK-3Beta。破坏这一点 途径导致微管相关的异常磷酸化 蛋白质tau，因此可能会损害轴突运输过程， 取决于微管的正常功能。 apoer2和vldlr都是 在胚胎神经元以及神经元的表面上表达大量表达 在成熟的大脑中，它们也可以充当受体 载脂蛋白E（APOE）。 APOE存在于三个主要同工型中。其中之一 同工型，APOE4在遗传上与晚期的阿尔茨海默氏病有关。 ApoE4易于携带的生化基础 阿尔茨海默氏病知之甚少。我们假设APOE4充当 竞争者的信号分子（例如reelin）并减少了其与 神经元表面的受体，从而损害生理 调节神经元转运和突触蛋白的信号通路 运输。该模型将提供一个机械基础 突触，与痴呆相关，并在斑块的形成之前 和神经纤维缠结，可以解释。电流的目标 建议是阐明被激活的细胞质信号通路 通过reelin与其受体在神经元细胞表面的结合，并与 研究reelin对轴突运输的影响，分子的活性 电机（例如动力蛋白和驱动蛋白），以及突触蛋白的运输 他们的目标站点。