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，但许多疾病相关途径仍处于- 探讨了该提案旨在了解与tau和TDP-43病理学相关的分子机制， 通过结合人类神经病理学和基因表达研究晚发性阿尔茨海默病（AD）的背景 数据与生物学验证在一个C. elegans蛋白毒性模型。在布莱恩博士的指导下 克雷默和德克·基恩，这个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基础上 并为她的职业生涯做好准备，利用C.作为一种模式的优雅 系统C.由于它们的简单性，秀丽线虫是研究人类疾病机制的理想系统。 转基因修饰，生命周期短，以及进行性神经变性的重演， 人类蛋白质病的特征五年培训计划包括由一名 建立了C.线虫研究技术，TDP-43分类 蛋白质病，在人体组织中实施免疫组织化学定量算法，以及 RNA-Seq数据的分析和解释。本次培训将为拉蒂默博士提供跨学科的 实现她作为一名独立医生的长期职业目标所需的技能和知识 科学家的专业知识，以推进AD病理生理学领域使用C。elegans模型 蛋白毒性，以联系人类病理学与潜在机制。 来自人类队列的数据表明TDP-43在AD神经病理学变化的临床表达中的作用。 该提案将解决tau和TDP-43协同作用以驱动神经变性以及 靶向两种毒性蛋白质可能比单独靶向任一种具有更强的保护作用。该项目建立 拉蒂默博士先前与克雷默博士和利亚奇科博士的工作证明了tau蛋白和 TDP-43在C.结合蛋白质毒性的线虫模型，以及成人思维变化的尸检数据 (ACT)这项研究是一项独特的、纵向的、以社区为基础的老年人队列研究，从西雅图地区招募， 其TDP-43病理学与痴呆和病理性tau增加相关。拉蒂默医生会检测 tau/TDP-43 C中tau或TDP-43神经毒性的遗传修饰剂。elegans模型（目标1），并确定 TDP-43和tau病理学是否在人脑组织中相关，利用ACT尸检的数据 队列（目标2）。然后，她将使用神经病理学数据选择ACT队列中用于RNA-Seq分析的病例 鉴定可在tau/TDP-43中生物学验证的tau和TDP-43蛋白毒性的新修饰剂， C. elegans模型（Aim 3）。这些目标的完成将为未来的独立资助奠定基础， 人类遗传和神经病理学数据加上C. elegans模型，并奠定了基础，为一个新的 产生可以在其他组群和模型系统中进一步评估的AD治疗剂。

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.