Developing MSUT2 Nanobodies for Targeting Pathological Tau in Alzheimer's Disease

摘要 在阿尔茨海默病（AD）和相关的tau蛋白病中，tau神经病理学与阿尔茨海默病（AD）的严重程度相关。 痴呆然而，AD和AD相关痴呆（ADRD）的干预措施仅限于治疗 这些症状不会直接改变tau蛋白的病理学或由此产生的神经变性。这 强调了对tau靶向疾病修饰治疗剂的需要。我们的工作证明了 MSUT 2控制哺乳动物大脑中神经元对tau毒性的易感性。的机理 tau蛋白病的MSUT 2调节涉及MSUT 2 CCCH结构域与poly（A）RNA的结合，如 CCCH结构域的缺失抑制tau蛋白病小鼠模型中的神经变性。的 抑制MSUT 2与poly（A）结合单链抗体或纳米抗体先导物的鉴定 RNA将提供一种干预tau蛋白病的生物手段。我们假设生物学 病理性tau沉积开始后MSUT 2/poly（A）RNA结合的拮抗作用将 逆转病理性tau蛋白的毒性后果。该提案的具体目标将在 有效和特异性的基于脑渗透生物学的方法，以靶向MSUT 2，并使用它们来 剖析MSUT 2活性和tau蛋白病之间的时间和机制关系。完成 所提出的项目的进一步研究也将进一步证明MSUT 2在tau蛋白病中的重要性。这 知识将为未来的转化研究奠定基础， 并进一步验证用于干预tau蛋白病的新的候选治疗靶点 紊乱

Abstract In Alzheimer’s disease (AD) and related tauopathies, tau neuropathology correlates with severity of dementia. However, interventions for AD and AD related dementias (ADRDs) are limited to treatment of symptoms that do not directly alter tau pathology or the resultant neurodegeneration. This underscores the need for tau-targeted disease-modifying therapeutics. Our work has demonstrated that MSUT2 controls neuronal susceptibility to tau toxicity in the mammalian brain. The mechanism of MSUT2 modulation of tauopathy involves the MSUT2 CCCH domain binding to poly(A) RNA, as deletion of the CCCH domain suppresses neurodegeneration in mouse models of tauopathy. The identification of single chain antibody or nanobody leads that inhibit MSUT2 from binding to poly(A) RNA will provide a biologic means of intervening against tauopathy. We hypothesize that biologic antagonism of MSUT2/poly(A) RNA-binding after onset of pathological tau deposition will reverse the toxic consequences of pathological tau. The specific aims of this proposal will develop potent and specific brain-penetrant biologic based approaches to target MSUT2 and use them to dissect the temporal and mechanistic relationship between MSUT2 activity and tauopathy. Completion of the project as proposed will also further demonstrate the importance of MSUT2 in tauopathy. This knowledge will set the stage for future translational studies by both generating MSUT2 specific lead biologic agents and further validating a novel candidate therapeutic target for intervention in tauopathy disorders.