Regulation of SORLA by beta-arrestin2

这项研究的最终目的是推进我们对阿尔茨海默病复杂性的理解 (AD)病理生理学，并提供宝贵的临床前信息的新的治疗策略。零星 AD涉及多种遗传风险因素。AD的最大遗传风险因素之一是SORL 1;相关性 SORL 1的遗传变异与迟发性AD之间的关系在全基因组中反复揭示， 协会研究。此外，SORL 1的无义和错义突变导致常染色体显性遗传， 早发性AD，支持该基因在AD中的病因学作用。SORL 1编码分选相关受体 与A重复序列（SORLA）蛋白，它通过调节AD发病机制发挥保护作用， 内吞功能和淀粉样β（Aβ）代谢。尽管其在AD发病机制中的重要性，我们的知识 SORLA如何受细胞内信号分子调节，以及这种调节与AD的相关性， 令人惊讶的稀缺。在我们的初步研究中，我们发现了SORLA和β arrestin 2之间的一种新的相互作用， （β ARR 2），一种多功能运输/信号转导衔接子，可能参与AD。我们的初步数据 表明β ARR 2破坏了SORLA的逆转录酶介导的逆行转运并降低了SORLA的稳定性。 此外，我们发现SORLA-β ARR 2相互作用的显著增加，这与SORLA-β ARR 2相互作用的减少相关。 与对照组相比，在AD受试者的死后脑组织中，SORLA-逆转录酶相互作用。 因此，我们发现了一种新的β ARR 2依赖的SORLA运输和稳定性调节， 到AD。在这个建议中，我们将确定这一病理生理意义和潜在机制， 新的监管和使用临床前试验，以探索其作为AD治疗靶点的潜力。在目标1中，我们 确定β ARR 2如何改变SORLA运输和稳定性，以破坏内体网络和Aβ 新陈代谢.在目标2中，我们将测试这种SORLA的β ARR 2依赖性调节是如何被细胞内 发信号。在目标3中，我们将探索靶向这种新的调节途径的治疗潜力， 使用动物模型改善AD相关缺陷。

The ultimate goal of this study is to advance our understanding of the complexity of Alzheimer’s disease (AD) pathophysiology and to provide invaluable preclinical information on new treatment strategies. Sporadic AD involves multiple genetic risk factors. One of the top genetic risk factors for AD is SORL1; association between genetic variants of SORL1 and late-onset AD has been repeatedly revealed in genome-wide association studies. Furthermore, nonsense and missense mutations of SORL1 cause autosomal dominant early-onset AD, supporting an etiological role of this gene in AD. SORL1 encodes the sorting-related receptor with A repeat (SORLA) protein, which exhibits a protective role in AD pathogenesis through regulation of endocytic function and amyloid β (Aβ) metabolism. Despite its importance in AD pathogenesis, our knowledge of how SORLA is regulated by intracellular signaling molecules and the relevance of this regulation to AD is surprisingly scarce. In our preliminary studies, we identified a novel interaction between SORLA and βarrestin2 (βARR2), a multifunctional trafficking/signaling adaptor that is potentially involved in AD. Our preliminary data suggest that βARR2 disrupts retromer-mediated retrograde transport of SORLA and reduces SORLA stability. Furthermore, we found a significant increase in the SORLA-βARR2 interaction, which correlates with a decrease in the SORLA-retromer interaction, in postmortem brain tissues of AD subjects when compared to controls. Therefore, we discovered a novel βARR2-dependent regulation of SORLA trafficking and stability that is relevant to AD. In this proposal, we will determine the pathophysiological significance and underlying mechanism of this novel regulation and use preclinical tests to explore its potential as a therapeutic target for AD. In Aim 1, we will determine how βARR2 alters SORLA trafficking and stability to disrupt the endosome network and Aβ metabolism. In Aim 2, we will test how this βARR2-dependent regulation of SORLA is modulated by intracellular signaling. In Aim 3, we will explore the therapeutic potential of targeting this novel regulatory pathway in ameliorating AD-related deficits using animal models.