Understanding the role of Eph signaling in Alzheimer's disease

项目总结 晚发性阿尔茨海默病(LOAD)是一种复杂的遗传疾病，被认为至少部分受到 跨越多个不同的基因座。全基因组关联研究(GWAS)帮助填补了缺失的空白， 通过发现几个新的LOAD基因。EPHA1，编码EPHA1受体，是 促红细胞生成素产生肝细胞(EPH)受体酪氨酸激酶家族被认为是一种潜在的 我们发现了GWA中的一个基因座，并随后发现了因果突变。从生理上讲，Eph受体家族 调节各种发育过程，特别是在中枢神经系统，控制神经元成熟，轴突引导 和突触的形成。两个成员EphA4和EphB2的异常信号已经被直接牵连到 β介导的突触功能障碍和行为障碍。至于EPHA1，其确切的分子性质 对AD的参与仍不确定。我们发现(初步数据)EPHA1水平可能在负荷中上调 这表明，信号的增加可能是一个或多个AD相关变化的基础。突变 (P460L)是EPHA1罕见的功能增益编码突变，支持这一结论。同舟共济 这些结果提示EPHA1在LOAD中的慢性激活作用。这意味着，在细胞内的14个受体中， Eph家族，3与负荷有关，无论是分子上还是基因上，暗示着一个更大的和 Eph信号在负荷发病机制中的全球作用。这项建议的总体目标是了解 特定Eph相关基因和相关途径，特别是变异特异性基因功能改变的影响 相关性、表达及其在负荷发病机制中的作用。鉴于Eph基因在正常细胞中的重要性 我们假设，改变蛋白质功能的编码突变，如EPHA1-P460L，将影响一个 或更多涉及负载的下游路径。最终，理解Eph途径的功能 可以为LOAD的治疗提供洞察力。我们将协调现有的下一代序列数据集 关于加勒比拉美裔、高加索和非裔美国人多个家庭和多民族病例对照研究 并测试Eph受体与负荷风险的关系。随后，我们将对分子进行表征 机制(S)参与了从EPHA1-P460L开始的已识别Eph变体的功能改变如何 在负荷发病机制中起作用。

PROJECT SUMMARY Late-onset Alzheimer’s disease (LOAD) is a genetically complex and thought to be influenced, at least in part, across a number of different loci. Genome-wide association studies (GWAS) have helped fill in the missing gaps, by uncovering several novel genes for LOAD. EPHA1, encoding for the EphA1 receptor, a member of the erythropoietin-producing hepatocellular (Eph) family of receptor tyrosine kinases was identified as a potential locus in a GWAS and subsequently causal mutations were found by us. Physiologically, the Eph receptor family regulates various developmental processes, especially in the CNS, controlling neuron maturation, axon guidance and synapse formation. Aberrant signaling by two members, EphA4 and EphB2, has been directly implicated in Aβ-mediated synaptic dysfunction and behavioral impairment. As for EphA1, the precise molecular nature of its involvement in AD remains uncertain. We find (preliminary data) that EphA1 levels may be upregulated in LOAD brain, suggesting that increased signaling may underlie one or more AD-associated changes. The mutation (P460L) we reported is a rare gain-of-function coding mutation for EphA1 supporting that conclusion. Together these results suggest a role for chronic activation of EphA1 in LOAD. This means that, of the 14 receptors in the Eph family, 3 have been associated with LOAD, either molecularly or genetically, hinting at a much larger and global role for Eph signaling in LOAD pathogenesis. The overall objective of this proposal is to understand the impact of altered function in specific Eph related genes and the related pathway, in particular variant-specific associations, expression and effect on LOAD pathogenesis. Given the importance of Eph genes in normal cell function, we hypothesize that coding mutations altering protein function, such as EphA1-P460L, will impact one or more downstream pathways involved in LOAD. Ultimately, understanding the function of the Eph-pathway may provide insight into the treatment of LOAD. We will harmonize existing next generation sequence datasets on multiplex Caribbean Hispanic, Caucasian and African American families and a multi-ethnic case-control set and test the association of Eph receptors with risk of LOAD. Subsequently, we will characterize the molecular mechanism(s) involved in altered function of identified Eph variants starting with EphA1-P460L how this contributes to LOAD pathogenesis.