Dysregulated Ribosomal Protein Synthesis in Amyloid and Tau Mouse Models

淀粉样蛋白和 Tau 小鼠模型中核糖体蛋白合成失调

• 批准号: 10201329
• 负责人: Eric Klann
• 金额: $ 43.59万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10201329
• 关键词: 5' Untranslated Regions; APP-PS1; Ablation; Address; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Appearance; Cell physiology; Cells; Chronic; Clinical; Cluster Analysis; Development; Disease; Drosophila genus; Exhibits; Frontotemporal Dementia; Functional disorder; Genetic; Genetic Translation; Genotype; Hippocampus (Brain); Human; Impairment; Investigation; Label; Memory; Memory Loss; Memory impairment; Messenger RNA; Modeling; Mus; Mutant Strains Mice; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Open Reading Frames; Pathologic; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phosphorylation; Phosphotransferases; Presenile Alzheimer Dementia; Prion Diseases; Process; Protein Biosynthesis; Proteins; Proteome; Proteomics; Regulation; Ribosomal Proteins; Ribosomes; Senile Plaques; Slice; Specificity; Subgroup; Symptoms; Synapses; Synaptic plasticity; Tauopathies; Technology; Testing; Time; Tissues; Translating; Translation Initiation; Translations; Work; advanced disease; age related; base; effective therapy; embryonic stem cell; experimental study; hyperphosphorylated tau; improved; insight; long term memory; mouse model; novel; novel therapeutics; prevent; protein function; proteostasis; response; stoichiometry; success; tau Proteins; tau dysfunction; therapeutic target

Abstract It is known that protein homeostasis is impaired in Alzheimer’s disease (AD) and frontotemporal dementia (FTD). A multitude of studies have indicated that the proteome is altered throughout the disease process, and ribosomal dysfunction occurs prior to advanced disease states. We have previously shown that de novo protein synthesis is impaired in APP/PS1 mutant mice, which express known human mutations associated with early-onset AD. Mounting evidence suggests changes in cell functioning occur decades prior to the development of symptoms in AD. In addition, the lack of success of clinical drug trials based on the amyloid hypothesis indicates greater understanding of the AD process is necessary to develop novel and effective therapies. To address these issues, we have used novel proteomic technology to label newly synthesized proteins in asymptomatic APP/PS1 mice, as well as symptomatic APP/PS1 mice that exhibit AD-like memory deficits. Our preliminary studies indicate that protein synthesis is dysregulated in these mice, and significant changes in the synthesis of protein components of the ribosome are observed even prior to symptom onset. As these findings may underlie the pathology of this proteopathy, we propose to investigate the impact of this ribosomal dysregulation and test our overall hypothesis that that age-dependent alterations observed in the synthesis of specific ribosomal proteins (RPs) in amyloid and tau model mice alter the translation of selective mRNAs that ultimately result in synaptic and memory impairments. Moreover, as RP synthesis has recently been shown to be dysregulated in the rTg4510 mouse model of AD- and FTD-like tauopathy, we hypothesize that alterations in RP synthesis in response to AD- and FTD-like tau dysregulation could impact ribosomal protein content, and similarly affect translational activity. We first will determine the RP content of functional ribosomes from asymptomatic and symptomatic APP/PS1 mice. Then, we will determine the translational activity of ribosomes from AD model mice. Finally, we will determine RP stoichiometry and translational activity of ribosomes from the K3 and PS19 mouse models of tauopathy and neurodegeneration. The results of these experiments will further our understanding of the neurodegenerative disease process, paving the way for similar investigations in AD and FTD patient cells, and subsequently identifying therapeutic targets for the treatment of AD and FTD.

摘要 已知蛋白质稳态在阿尔茨海默病（AD）和额颞叶痴呆（FTD）中受损。 大量研究表明，蛋白质组在整个疾病过程中发生变化，而核糖体蛋白质组在疾病过程中发生变化。 功能障碍发生在晚期疾病状态之前。我们以前已经证明，从头蛋白质合成， 在APP/PS1突变小鼠中受损，这些小鼠表达与早发性AD相关的已知人类突变。 越来越多的证据表明，细胞功能的变化发生在症状出现之前的几十年 在AD中。此外，基于淀粉样蛋白假说的临床药物试验缺乏成功，这表明 对AD过程的理解对于开发新的和有效的疗法是必要的。为了解决这些问题， 我们已经使用新的蛋白质组学技术来标记无症状APP/PS1小鼠中新合成的蛋白质， 以及表现出AD样记忆缺陷的症状性APP/PS1小鼠。我们的初步研究表明， 在这些小鼠中蛋白质合成失调， 甚至在症状发作之前就观察到核糖体的变化。由于这些发现可能是这种病理学的基础， 蛋白质病，我们建议调查这种核糖体失调的影响，并测试我们的整体 假设在特定核糖体蛋白合成中观察到的年龄依赖性改变 (RPs)在淀粉样蛋白和tau蛋白模型小鼠中， 突触和记忆障碍此外，由于RP合成最近已被证明是失调， AD样和FTD样tau蛋白病rTg 4510小鼠模型，我们假设 对AD和FTD样tau失调的反应可能影响核糖体蛋白含量， 翻译活性我们首先将确定无症状和无症状的功能核糖体的RP含量 症状APP/PS1小鼠。然后，我们将测定AD模型小鼠核糖体的翻译活性。 最后，我们将测定K3和PS19小鼠核糖体的RP化学计量和翻译活性 tau蛋白病和神经变性的模型。这些实验的结果将进一步加深我们对 神经退行性疾病过程，为在AD和FTD患者细胞中进行类似研究铺平了道路， 并随后鉴定用于治疗AD和FTD的治疗靶点。