Elucidating the Effects of Post-Translational Modifications on Tau Binding to F-actin and PSD95

阐明翻译后修饰对 Tau 与 F-肌动蛋白和 PSD95 结合的影响

基本信息

批准号：
10606093
负责人：
Chiara Diamante Mancinelli
金额：
$ 4.77万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-19 至 2025-12-18
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10606093
关键词：
Acetylation Actins Address Affect Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease patient Amyloid beta-Protein Automobile Driving Behavior Binding Biological Biological Assay Biophysics Brain Bundling Cells Cellular Assay Chemicals Clinical Trials Cognitive Complement Data Development Disease F-Actin Hyperemia Impaired cognition In Vitro Letters Lysine Maps Mediating Microfilaments Microtubule Stabilization Mutation N-Methyl-D-Aspartate Receptors N-terminal NMR Spectroscopy Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Nuclear Magnetic Resonance Pathologic Pathology Phosphorylation Physiological Play Post-Translational Protein Processing Process Proteins Receptor Activation Reporting Research Resolution Role Sampling Sedimentation process Senile Plaques Side Structure Structure-Activity Relationship Tauopathies Techniques Testing Therapeutic Vertebral column biophysical techniques design effective therapy experimental study improved mimetics monomer mutant neurofibrillary tangle formation neuron loss neurotoxicity new therapeutic target novel postsynaptic density protein pre-clinical tau Proteins tau aggregation tau function tau interaction tau microtubule binding domain tau-1 tau-microtubule interaction

项目摘要

Project Summary/Abstract Alzheimer’s disease (AD) and other tau-related neurodegenerative diseases are characterized by neurofibrillary tangles which are composed of aggregates of the microtubule associated protein tau. The accumulation of these tangles contributes to neuronal death and cognitive decline. While millions nationally are plagued by Alzheimer’s, therapeutic efforts focusing on one of the main hallmarks of the disease, amyloid-beta (Aβ) plaques, have remained unsuccessful. The lack of correlation between treatment and robust cognitive improvement during these clinical trials highlight the urgent need to elucidate the preclinical mechanistic changes driving disease manifestation. The physiological roles of tau include the stabilization of microtubules, and bundling of F-actin filaments. While tau-microtubule interactions are well-studied, tau interactions with F- actin are more poorly understood, but are reported to drive the development of pathological species such as Hirano bodies, actin inclusions found in AD brains and other tauopathies. Tau can form other functional or pathological interactions, including recently reported binding to post-synaptic density protein 95 (PSD-95), which was shown to interfere with functional hyperemia and promote the neurotoxicity induced by amyloid- beta. Tau is also modified by a rich array of post-translational modifications (PTMs), which have been shown to alter normal and pathological tau interactions. This proposal will test the central hypothesis that tau PTMs within the critical PHF6 and PHF6* hexapeptide motifs modulate tau interactions with binding partners such as PSD-95 and F-actin and thereby contribute to the role of these partners, as well of changes in tau structure and function, in specific processes associated with disease manifestation. Using biophysical methods, including nuclear magnetic resonance (NMR) spectroscopy, I will characterize the interactions of tau with F-actin and PSD-95 and assess the effects of PTMs located within the PHF6 and PHF6* motifs on these interactions. Our structural observations, complemented by functional studies performed both by myself and our collaborators, will contribute to a deeper understanding of the mechanistic changes in tau behavior that drive the manifestation of AD and other tauopathies, and facilitate the development of novel therapeutic targets for the treatment of tau-based neurodegeneration.

项目概要/摘要阿尔茨海默病 (AD) 和其他 tau 相关神经退行性疾病的特点是由微管相关蛋白 tau 聚集体组成的神经原纤维缠结。这些缠结的积累会导致神经死亡和认知能力下降，而全国有数百万人患有这种疾病。受阿尔茨海默氏症困扰，治疗工作集中在该疾病的主要特征之一——淀粉样蛋白上（Aβ）斑块仍然不成功治疗和稳健认知之间缺乏相关性。这些临床试验期间的改进凸显了阐明临床前机制的迫切需要 tau 蛋白的生理作用包括稳定微管、虽然 tau 微管相互作用已得到充分研究，但 tau 与 F- 肌动蛋白丝的相互作用。人们对肌动蛋白知之甚少，但据报道可以驱动病理物种的发展，例如平野小体、AD 大脑中发现的肌动蛋白内含物和其他 tau 蛋白病可以形成其他功能性或功能性蛋白病。病理学相互作用，包括最近报道的与突触后密度蛋白 95 (PSD-95) 的结合，它被证明可以干扰功能性充血并促进淀粉样蛋白诱导的神经毒性 beta.Tau 还受到一系列丰富的翻译后修饰 (PTM) 的修饰，这些修饰已被证明改变正常和病理性 tau 相互作用该提案将检验 tau PTM 的中心假设。在关键的 PHF6 和 PHF6* 六肽基序内调节 tau 与结合伙伴的相互作用例如 PSD-95 和 F-肌动蛋白，从而有助于这些合作伙伴的作用，以及改变 tau 蛋白的结构和功能，在与疾病表现相关的特定过程中。生物物理方法，包括核磁共振（NMR）波谱，我将描述 tau 与 F-肌动蛋白和 PSD-95 的相互作用，并评估位于 PHF6 内的 PTM 的影响和我们对这些相互作用的结构观察，并辅以功能研究。由我和我们的合作者共同完成，将有助于更深入地理解机械 tau 蛋白行为的变化会导致 AD 和其他 tau 蛋白病的表现，并促进开发治疗基于 tau 的神经变性的新治疗靶点。