Identifying kinase signaling pathways linked to tau-mediated neurodegeneration

识别与 tau 介导的神经变性相关的激酶信号通路

基本信息

批准号：
10753257
负责人：
Todd Jonathan Cohen
金额：
$ 25.13万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10753257
关键词：
Ablation Acceleration Acetylation Acetyltransferase Address Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Binding Brain Brain Pathology CREBBP gene Cell physiology Cognition Coupled Cryoelectron Microscopy Cytoplasm Data Deacetylase Deacetylation Disease Progression Engineering Enzymes Event Functional disorder Future Genes Genetic Genetic Transcription Goals HDAC3 gene HDAC4 gene HDAC6 gene Heart Histone Deacetylase Human Idiopathic Parkinson Disease Impaired cognition Individual LRRK2 gene Light Link Lysine Mass Spectrum Analysis Measures Mediating Mediator Microtubules Modeling Modification Mus Nerve Degeneration Neurodegenerative Disorders Neuronal Dysfunction Neurons Nuclear Parkinson Disease Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Phosphotransferases Post-Translational Protein Processing Process Property Role Signal Pathway Signal Transduction Sirtuins Structure Synapses Tauopathies Therapeutic Toxic effect combinatorial drug discovery in vivo induced pluripotent stem cell innovation mouse model novel therapeutics prevent synaptic function synergism tau Proteins tau aggregation tau function tau mutation tau-1 upstream kinase virtual

项目摘要

PROJECT SUMMARY At the heart of Alzheimer’s (AD) pathogenesis, tau pathology is linked to neurodegeneration and cognitive decline. We have spent the last decade addressing how tau exerts its toxicity in AD. Among the many tau post- translational modifications (PTMs) that are now known to co-occur and target tau, acetylation of tau’s lysines, which have emerged from recent cryo-EM and mass spectrometry studies, is a particularly relevant and attractive target. Coupled with the fact that acetylation accelerates tau aggregation, prevents normal microtubule binding, and induces prominent AD-like deficits including synaptic dysfunction and cognitive decline, these properties would appear to set this particular PTM apart from many of the other tau PTMs that are known to regulate tau. While acetylated tau is common to virtually all sporadic AD brains, there remain few reliable models to unravel the signaling events and enzymes that converge on this idea. In our view, this gap needs to be overcome if we hope to unravel mechanisms that drive tau pathogenesis. We identified a new signaling pathway in which the Parkinson’s disease (PD)-relevant kinase LRRK2 acts upstream to regulate HDACs and therefore indirectly controls tau acetylation. We hypothesize that LRRK2 and other related “HDAC kinases” act as master regulators of HDAC function, with their end goal of preventing the accumulation of acetylated tau and thereby protecting against tau toxicity. In Aim-1, we develop a new model based on an engineered cytoplasmic CBP acetyltransferase to precisely target cytoplasmic tau and then assess the extent of tau pathology, synaptic dysfunction, tau seeding, and tau propagation. Having narrowed in on HDACs 3/6 as the only tau-associated HDACs among all human HDACs, we will deliver them to neurons and determine whether synergism among HDACs converges onto tau to suppress its toxicity. In Aim-2, we focus on the upstream kinases that coordinate HDAC activity. We explore LRRK2 as a very attractive hit identified in a mini screen that modulates HDAC3/6 function. We will manipulate LRRK2 function in mouse neurons, mice, and human iPSC neurons to evaluate downstream consequences on HDACs and tau. Our proposal will shed light, not only on AD-relevant HDACs, but also open up new therapeutic avenues (e.g., the targeting of upstream kinases) to suppress toxic tau species in the brain. This proposal is therefore both innovative and significant since upstream HDAC regulatory kinases including LRRK2 and PKC hold promise as unanticipated regulators of HDAC activity. This will expand our repertoire of targetable pathways in tauopathies that include AD and even PD as well.

项目概要 tau 蛋白病理学是阿尔茨海默病 (AD) 发病机制的核心，与神经退行性变和认知有关在过去的十年里，我们一直在研究 tau 蛋白如何在 AD 中发挥毒性。目前已知翻译修饰 (PTM) 会同时发生并以 tau 为目标，tau 赖氨酸的乙酰化，最近的冷冻电镜和质谱研究中出现的一个特别相关且加上乙酰化会加速 tau 蛋白聚集，从而阻碍正常现象。微管结合，并诱导显着的 AD 样缺陷，包括突触功能障碍和认知功能障碍下降，这些特性似乎将这个特定的 PTM 与许多其他 tau PTM 区分开来。众所周知，乙酰化 tau 蛋白在几乎所有散发性 AD 大脑中都很常见，但这种情况仍然很少。在我们看来，这一差距是通过可靠的模型来揭示集中于这一想法的信号事件和酶的。如果我们希望阐明驱动 tau 发病机制的机制，就需要克服这一难题。帕金森病 (PD) 相关激酶 LRRK2 在上游发挥调节作用的信号通路 HDAC 因此间接控制 tau 乙酰化。我们勇敢地说 LRRK2 和其他相关的“HDAC”。激酶”作为 HDAC 功能的主要调节因子，其最终目标是防止在 Aim-1 中，我们开发了一种基于乙酰化 tau 的新模型。改造细胞质 CBP 乙酰转移酶以精确靶向细胞质 tau，然后评估其程度 tau 病理学、突触功能障碍、tau 播种和 tau 传播已缩小为 HDAC 3/6。所有人类 HDAC 中唯一与 tau 相关的 HDAC，我们将把它们传递到神经元并确定 HDAC 之间的协同作用是否会收敛于 tau 蛋白以抑制其毒性。我们探索了 LRRK2 作为在 mini 中发现的一个非常有吸引力的命中。我们将操纵小鼠神经元、小鼠和小鼠中的 LRRK2 功能。人类 iPSC 神经元评估对 HDAC 和 tau 的下游影响不仅针对 AD 相关的 HDAC，而且还开辟了新的治疗途径（例如，靶向上游因此，这一提议既具有创新性又具有重要意义。因为包括 LRRK2 和 PKC 在内的上游 HDAC 调节激酶有望成为意想不到的调节剂 HDAC 活性的研究将扩大我们在 tau 蛋白病中的靶向途径，包括 AD 和甚至PD也是如此。