Functional Validation of the CD2AP Susceptibility Network in Alzheimer's Disease

 描述（由申请人提供）：全基因组关联研究（GWAS）最近在22个基因组位点鉴定了与阿尔茨海默病（AD）易感性相关的变异。与其他常见、复杂的遗传性疾病相似，AD的特征在于显著的基因座异质性和多基因易感性。接下来的关键步骤包括理解基因机制和阐明定义介导AD风险的功能途径的遗传相互作用。我们已经开发出一种成功的跨物种验证策略，将新出现的易感性候选者与果蝇（Drosophila melanogaster）中基因和通路的功能解剖联系起来。迄今为止，我们对AD GWAS候选基因的研究表明，易感性网络由CD 2AP和相关细胞粘附介质（包括CASS 4、FERMT 2和PTK 2B）以及内吞作用（包括PICALM、BIN 1、AP-2α和RIN 3）组成。编码的蛋白质概括了一个假定的相互作用网络，支持它们在神经系统健康和疾病中的协调功能。在初步研究中，我们进一步表明，CD 2AP，类似于其他网络候选者，定位于突触，与突触囊泡蛋白相关联，并且功能丧失既损害突触可塑性又增强Tau的神经毒性，其形成AD的神经元缠结病理特征。该提案的总体目标是扩展我们对定义CD 2AP易感性网络及其对AD发病机制的贡献的基因和功能相互作用的理解。我们假设，CD 2AP调节通路内的功能障碍减弱了突触功效，并导致AD中对Tau诱导的神经元损伤的脆弱性增强。我们将首先（AIM 1）利用果蝇中可获得的快速而强大的遗传学，对CD 2AP易感性网络中涉及的保守基因进行系统的功能解剖，包括通路相互作用的上位性作图。接下来（AIM 2），我们将采用小鼠模型进一步阐明CD 2AP在哺乳动物突触和Tau介导的神经变性中的作用。最后（AIM 3），为了翻译我们的发现，动物模型研究将与人类队列分析相结合，检查与年龄相关的突触丢失，AD神经病理学负担和导致的认知障碍相关的转录本和蛋白质的调节变化。影响：通过将新兴的人类基因组数据与苍蝇，小鼠和人脑的功能研究相结合，我们将阐明CD 2AP易感性网络并定义其在突触健康，Tau病理学和AD风险中的作用，提供丰富的临床前数据组合以支持新的治疗靶点。

 DESCRIPTION (provided by applicant): Genome-wide association studies (GWAS) have recently identified variants at 22 genomic loci associated with Alzheimer's disease (AD) susceptibility. Similar to other common, complex genetic disorders, AD is characterized by substantial locus heterogeneity and polygenic susceptibility. The critical next steps include understanding gene mechanisms and elucidating the genetic interactions that define functional pathways mediating AD risk. We have developed a successful cross-species validation strategy that links emerging susceptibility candidates to functional dissection of genes and pathways in the fruit fly, Drosophila melanogaster. Our studies to date of candidate genes from AD GWAS implicate a susceptibility network comprised of CD2AP and related mediators of cell adhesion, including CASS4, FERMT2, and PTK2B, and endocytosis, including PICALM, BIN1, AP-2α, and RIN3. The encoded proteins recapitulate a putative interaction network, supporting their coordinate function in nervous system health and disease. In preliminary studies, we further show that CD2AP, similar to other network candidates, localizes to the synapse, associates with synaptic vesicle proteins, and loss-of-function both impairs synaptic plasticity and enhances the neurotoxicity of Tau, which forms neurofibrillary tangle pathology characteristic of AD. The overall goal of this proposal is to extend our understanding of the genes and functional interactions that define the CD2AP susceptibility network and its contribution to AD pathogenesis. We hypothesize that dysfunction within the CD2AP regulatory pathway attenuates synaptic efficacy, and leads to enhanced vulnerability to Tau- induced neuronal injury in AD. We will first (AIM 1) exploit the rapid and powerful genetics available in flies for systematic functional dissection of conserved genes implicated in the CD2AP susceptibility network including epistatic mapping of pathway interactions. Next (AIM 2), we will employ mouse models to further elucidate the role of CD2AP at mammalian synapses and in Tau-mediated neurodegeneration. Lastly (AIM 3), for translation of our findings, the animal model studies will be coupled with analyses in human cohorts, examining regulatory changes in transcripts and proteins in relation to age-related synaptic loss, AD neuropathologic burden, and resulting cognitive impairment. IMPACT: By integrating emerging human genomic data with functional investigation in flies, mice and human brains, we will elucidate the CD2AP susceptibility network and define its role in synaptic health, Tau pathology, and AD risk, delivering a rich portfolio of preclinical data to support new therapeutic targets.