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

• 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
• 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' s Disease; Alzheimer' s disease brain; Alzheimer' 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

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.

项目摘要 阿尔茨海默氏症（AD）发病机理的核心，tau病理与神经变性和认知有关 衰退。在过去的十年中，我们已经解决了Tau如何在AD中施加毒性。在许多tau邮政中 现在已知可以共同发生和靶向tau的翻译修饰（PTMS），tau赖氨酸的乙酰化， 来自最近的低温EM和质谱研究已经出现的，这是一个特别相关的， 有吸引力的目标。再加上乙酰化加速tau聚集的事实可防止正常 微管结合，并诱导突出的广告样式定义包括突触功能障碍和认知 下降，这些特性似乎将这种特殊的PTM与其他许多tau PTM区分开 已知会调节tau。乙酰化的tau几乎是所有零星广告大脑的常见，但很少有 可靠的模型，以揭示在此想法上融合的信号事件和酶。在我们看来，这个差距 如果我们希望揭开驱动tau发病机理的机制，则需要克服。我们确定了一个新的 帕金森氏病（PD） - Relevant激酶LRRK2的信号传导途径在上游进行调节 HDACS，因此间接控制Tau乙酰化。我们假设LRRK2和其他相关的“ HDAC 激酶”是HDAC功能的主要调节剂，其最终目标是防止积累 乙酰化的tau，从而防止tau毒性。在AIM-1中，我们基于一个 设计的细胞质CBP乙酰转移酶精确靶向细胞质TAU，然后评估程度 tau病理学，突触功能障碍，tau播种和tau繁殖。在3/6上缩小了HDACS 在所有人类HDAC中，唯一与Tau相关的HDAC，我们将将其传递给神经元并确定 HDAC中的协同作用是否会收敛到TAU以抑制其毒性。在AIM-2中，我们专注于 上游的激酶，可协调HDAC活性。我们探索LRRK2是在迷你中发现的非常吸引人的命中 屏幕调节HDAC3/6功能。我们将操纵小鼠神经元，小鼠和 人IPSC神经元评估对HDAC和TAU的下游后果。我们的建议将浮出水面， 不仅在与广告相关的HDAC上，而且还打开了新的治疗途径（例如，上游的靶向 激酶）以抑制大脑中的有毒tau物种。因此，该提议既具有创新又具有重要意义 由于包括LRRK2和PKC在内的上游HDAC调节激酶作为意外调节器有望 HDAC活性。这将扩大我们在包括广告和包括AD和 甚至PD。