GDE and Neurodegenerative Diseases

 描述（由申请人提供）：该提案设想了一种基于新发现的可药物化酶的人类阿尔茨海默病的范式转变。我们目前对AD的理解提出了淀粉样蛋白Aβ积累的核心作用（1），但在理解导致散发性AD中Aβ增加的机制方面仍有很大的进展。此外，AD病理学的许多方面不能简单地理解为Aβ蓄积的结果，并表明其他分子机制有助于发病机制。还非常需要能够合理地与发病机制联系起来的诊断方法。最重要的是需要有效的治疗方法。这些挑战是该领域众所周知的。我们看到了推进AD研究的独特机会，该研究建立在发现一种新型酶家族的基础上，该酶家族控制着大脑发育中几种最重要的信号通路。GDE催化磷酸二酯键的裂解，磷酸二酯键将一类细胞外蛋白质连接到细胞表面（2）。这些GPI连接的蛋白质充当Notch、音刺猬、成纤维细胞生长因子、Wnt、肝配蛋白（EphA5）、睫状神经营养因子受体（CNTF）、胶质源性神经营养因子和接触素的激活剂或抑制剂。GDE在神经退行性变中的作用是偶然发现的，即成年大脑中GDE的条件性缺失导致深刻的年龄依赖性神经退行性变化，包括人类神经退行性疾病的许多标志。我们假设GDE功能的丧失有助于人类神经退行性疾病。该方法利用了GDE活性的幸运结果，即将底物蛋白脱落到细胞外区室和CSF中。这产生了GDE活性的“生物标志物”。作为概念的证明，我们已经确定朊病毒蛋白是GDE的底物。朊病毒蛋白存在于CSF中，其水平在人类AD受试者中降低，与认知下降平行（3），最近的研究表明朊病毒蛋白参与AD中突触强度的病理性降低和Aβ生成的增强（4，5）。我们将扩大这一先例，使用无偏见的方法，以确定GDE基板在CSF和大脑的正常和患病的人。这些生物标志物将识别特定的信号传导途径，从而GDE功能在AD中始终被破坏。如果成功的话，这种方法将提供与疾病机制相关的生物标志物，可以与GDE途径的调节剂结合，作为AD的新的基于机制的诊断和治疗方法。

 DESCRIPTION (provided by applicant): This proposal imagines a paradigm shift for understanding human Alzheimer's disease that is based on a newly discovered, druggable enzyme. Our current understanding of AD proposes a central role for the accumulation of amyloid Aβ (1), but there is great need for advances in understanding mechanisms that cause increases of Aβ in sporadic AD. Moreover, there are many aspects of the pathology of AD that cannot be simply understood as a consequence of Aβ accumulation, and suggest other molecular mechanisms contribute to pathogenesis. There is also a great need for diagnostics that can be rationally linked to pathogenesis. Most of all there is a need for effective therapeutics. These challenges are well known to the field. We see a unique opportunity to advance AD research that builds on the discovery of a novel enzyme family that controls several of the most important signalling pathways in brain development. GDEs catalyze cleavage of the phosphodiester bond that links a class of extracellular proteins to the cell surface (2). These GPI-linked proteins act as activators or inhibitors of Notch, sonic hedgehog, fibroblast growth factor, Wnt, ephrin (EphA5), ciliary neurotrophic factor receptor (CNTF), glial derived neurotrophic factor, and contactins. The role of GDEs in neurodegeneration was made serendipitously with the discovery that conditional deletion of GDE in adult brain results in profound, age-dependent neurodegenerative changes that include many of the hallmarks of human neurodegenerative disease. We hypothesize that loss of GDE function contributes to human neurodegenerative disease. The approach exploits the fortunate consequence of GDE activity, which is to shed substrate proteins into the extracellular compartment and CSF. This creates "biomarkers" of GDE activity. As proof of concept, we have determined that prion protein is a substrate of GDE. Prion protein is present in the CSF at levels that are reduced in human AD subjects in parallel with cognitive decline(3), and recent studies implicate prion protein in pathological reduction of synaptic strength and enhanced Aβ generation in AD(4, 5). We will expand this precedent using non-biased methods to identify GDE substrates in CSF and brain of normal and diseased humans. These biomarkers will identify specific signalling pathways consequent to GDE function that are consistently disrupted in AD. Where successful, this approach will provide mechanism-linked biomarkers of disease that can be combined with modulators of the GDE pathway as new mechanism-based diagnostics and therapeutics for AD.