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病中，tau神经病理与 痴呆症。然而，对AD和AD相关痴呆(ADRD)的干预仅限于治疗 不会直接改变tau病理或由此导致的神经变性的症状。这 强调了以tau为靶点的疾病修正疗法的必要性。我们的工作证明了 在哺乳动物的大脑中，MSUT2控制神经元对tau毒性的敏感性。它的作用机制 MSUT2调节互变涉及MSUT2 CCCH结构域与Poly(A)RNA结合，AS CCCH结构域的缺失抑制了脊椎病小鼠模型的神经退行性变。这个 抑制MSUT2与Poly(A)结合的单链抗体或纳米体导联的鉴定 RNA将提供一种生物手段来干预变态反应。我们假设生物学上的 病理性tau沉积后MSUT2/聚(A)RNA结合的拮抗作用 逆转病理性tau的毒性后果。这项建议的具体目标将会发展。 针对MSUT2的有效和特定的脑穿透生物方法并利用它们 剖析MSUT2活动与直肠反复症之间的时间和机制关系。完成 也将进一步证明MSUT2在直立面疗法中的重要性。这 知识将通过生成MSUT2特定线索为未来的翻译研究奠定基础 生物制剂和进一步验证干预直肠痉挛的新候选治疗靶点 精神错乱。

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.