Molecular Mechanisms of Synergistic TDP-43 and Tau Proteotoxicity in Alzheimer's Disease

摘要 目前还没有针对AD的疾病修饰疗法，但许多与疾病相关的途径仍处于- 探索过了。这项建议试图了解与tau和tdp-43病理相关的分子机制。 结合人类神经病理学和基因表达研究迟发性阿尔茨海默病(AD)的发病背景 在线虫蛋白毒性模型中进行生物学验证的数据。在Brain博士的指导下 克莱默和德克·基恩，这项培训和研究计划将建立在拉蒂默博士在神经病理学方面的专业知识的基础上 并以线虫为模型研究与AD相关的蛋白毒素途径，为她的职业生涯做好准备 系统。鉴于线虫的易感性，线虫是研究人类疾病机制的理想系统。 转基因修饰，短生命周期，以及进行性神经变性的重演，即 人类蛋白质病的特点。这项为期五年的培训计划包括由 在线虫研究技术、TDP-43分类方面建立了专家团队和指导 蛋白质病，人体组织免疫组织化学定量算法的实施，以及 RNA-Seq数据的分析和解释这次培训将为拉蒂默博士提供跨学科的 实现作为一名独立医生的长期职业目标所需的技能和知识 具有利用线虫模型推进AD病理生理学领域的专业知识的科学家 蛋白质毒性将人类病理与潜在机制联系起来。 来自人类队列的数据表明，TDP-43在AD神经病理改变的临床表达中发挥了作用。 这项提案将解决tau和TDP-43协同驱动神经退行性变的假设，以及 同时针对两种有毒蛋白质可能比单独针对其中任何一种具有更强的保护作用。该项目将构建 关于Latimer博士之前与Kraemer博士和Liachko博士一起证明tau和Liachko之间的协同作用的工作 在线虫联合蛋白毒性模型中的TDP-43，以及成人思维变化的尸检数据 (ACT)研究是从西雅图地区招募的独特的、以社区为基础的老年人队列，在 其中TDP-43的病理与痴呆症和病理tau的增加有关。拉蒂默博士将测试已知 在tau/TDP-43线虫模型中tau或TDP-43神经毒性的遗传修饰物(目标1)并确定 利用ACT尸检数据，TDP-43和tau病理在人脑组织中是否相关 队列(目标2)。然后，她将使用神经病理学数据来选择ACT队列中的RNA-Seq分析病例 确定可在tau/TDP-43中生物学验证的tau和TDP-43蛋白毒性的新修饰物 线虫模型(目标3)。这些目标的完成将为未来独立使用资金奠定基础 人类遗传和神经病理学数据与线虫模型相结合，为新的 AD疗法的产生，可以在其他队列和模型系统中进一步评估。

Abstract There are currently no disease modifying therapies for AD but many disease-relevant pathways remain under- explored. This proposal seeks to understand the molecular mechanisms relating tau and TDP-43 pathology in the context of late-onset Alzheimer’s disease (AD) by combining human neuropathology and gene expression data with biological validation in a C. elegans model of proteotoxicity. Under the mentorship of Drs. Brain Kraemer and Dirk Keene, this training and research plan will build on Dr. Latimer’s expertise in neuropathology and prepare her for a career studying the proteotoxic pathways relevant to AD using C. elegans as a model system. C. elegans represent an ideal system for investigating mechanisms of human disease given their ease of transgenic modification, short life cycle, and recapitulation of the progressive neurodegeneration that is characteristic of human proteinopathies. The five-year training plan includes research mentored by an established team of experts and instruction in C. elegans research techniques, classification of TDP-43 proteinopathy, implementation of quantitative algorithms for immunohistochemistry in human tissue, and analysis and interpretation of RNA-Seq data. This training will provide Dr. Latimer with the interdisciplinary skills and knowledge necessary to achieve her long-term career goal to succeed as an independent physician scientist with the expertise to advance the field of AD pathophysiology using C. elegans models of proteotoxicity to link human pathology with the underlying mechanisms. Data from human cohorts suggest a role for TDP-43 in the clinical expression of AD neuropathologic change. This proposal will address the hypotheses that tau and TDP-43 synergize to drive neurodegeneration and that targeting both toxic proteins may have stronger protective effects than targeting either alone. The project builds on Dr. Latimer’s previous work with Drs. Kraemer and Liachko demonstrating the synergism between tau and TDP-43 in a C. elegans model of combined proteotoxicity, and autopsy data in the Adult Changes in Thought (ACT) study, a unique, longitudinal community-based cohort of older adults recruited from the Seattle area, in which TDP-43 pathology is associated with dementia and increased pathologic tau. Dr. Latimer will test known genetic modifiers of tau or TDP-43 neurotoxicity in the tau/TDP-43 C. elegans model (Aim 1) and determine whether TDP-43 and tau pathology correlate in human brain tissue, leveraging data from the ACT autopsy cohort (Aim 2). She will then use neuropathology data to select cases for RNA-Seq analysis in the ACT cohort to identify novel modifiers of tau and TDP-43 proteotoxicity that can be biologically validated in the tau/TDP-43 C. elegans model (Aim 3). Completion of the aims will set the stage for future independent funding using human genetic and neuropathologic data coupled with C. elegans models and lay the foundation for a new generation of AD therapeutics that can be further evaluated in other cohorts and model systems.