APO E Receptors and Modulation of Fast Axonal Transport

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 被发现参与信号转导途径， 大脑的发展。Reelin是一种大的分泌性蛋白质， 与脂蛋白相似，不参与脂质转运，与 该基因家族的两个成员的胞外结构域，称为VLDL 受体（VLDLR）和ApoE受体2（ApoER 2）。该配体的结合激活 一种细胞质信号级联，显然涉及酪氨酸激酶， 以及丝氨酸/苏氨酸激酶Cdk 5和GSK-3 β。破坏这种 途径导致微管相关蛋白的异常磷酸化 tau蛋白，因此可能损害轴突运输过程， 依赖于微管的正常功能。ApoER 2和VLDLR都是 在胚胎神经元表面和神经元上大量表达 在成熟的大脑中，它们也可以作为受体， 载脂蛋白E（ApoE）。ApoE有三种主要的亚型。其中一 ApoE 4与迟发性阿尔茨海默病在遗传上相关。 ApoE 4使其携带者易患晚发性 阿尔茨海默病是知之甚少。我们假设ApoE 4作为一种 竞争信号分子，如Reelin，并减少其结合 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 运输这一模型将提供一个机械基础， 突触，这与痴呆症相关，并在斑块形成之前 和神经系统缠结都可以解释当前的目标 一个建议是阐明细胞质信号通路， 通过Reelin与神经元细胞表面的受体结合， 研究了Reelin对轴突运输、分子生物学活性、神经元功能的影响， 马达，如动力蛋白和驱动蛋白，以及突触蛋白的运输， 他们的目标网站。

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.