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

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

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.

项目总结/摘要 阿尔茨海默病（AD）和其他tau相关的神经退行性疾病的特征在于： 神经原纤维缠结，由微管相关蛋白tau的聚集体组成。的 这些缠结的积累导致神经元死亡和认知能力下降。虽然全国有数百万人 受阿尔茨海默氏症困扰，治疗工作集中在疾病的主要标志之一，淀粉样β蛋白 （Aβ）斑块，仍然不成功。治疗与强大的认知能力之间缺乏相关性 在这些临床试验中的改进突出了阐明临床前机制的迫切需要， 改变驱动疾病表现。tau的生理作用包括微管的稳定， 和成束的F-肌动蛋白丝。虽然tau-微管相互作用得到了充分研究，但tau与F- 肌动蛋白的了解更少，但据报道，推动发展的病理物种，如 平野小体，在AD脑和其他tau蛋白病中发现的肌动蛋白包涵体。Tau可以形成其他功能或 病理相互作用，包括最近报道的与突触后密度蛋白95（PSD-95）的结合， 其显示干扰功能性充血并促进淀粉样蛋白诱导的神经毒性， β的Tau还被一系列丰富的翻译后修饰（PTM）所修饰，这些修饰已被证明是 改变正常和病理性tau相互作用。这项提议将检验tau蛋白翻译后修饰的中心假设， 在关键的PHF 6和PHF 6 * 六肽基序中，调节tau与结合伴侣的相互作用 如PSD-95和F-肌动蛋白，从而有助于这些伙伴的作用，以及 tau结构和功能，在与疾病表现相关的特定过程中。使用 生物物理方法，包括核磁共振（NMR）光谱，我将表征 tau与F-肌动蛋白和PSD-95的相互作用，并评估位于PHF 6内的PTM的作用， PHF 6 * 基序对这些相互作用的影响。我们的结构观察加上功能研究 由我自己和我们的合作者进行，将有助于更深入地了解机械 tau行为的变化驱动AD和其他tau蛋白病的表现，并促进 开发用于治疗基于tau的神经变性的新型治疗靶点。