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

基本信息

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
项目类别：
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&apos Untranslated Regions APP-PS1 Ablation Address Affect Age Alzheimer&apos s Disease Alzheimer&apos 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

项目摘要

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.

抽象的众所周知，阿尔茨海默氏病（AD）和额颞痴呆（FTD）受损蛋白质稳态。大量研究表明，在整个疾病过程中，蛋白质组发生了变化，核糖体发生了功能障碍发生在晚期疾病状态之前。我们以前已经表明从头蛋白质合成在APP/PS1突变小鼠中受到损害，该突变小鼠表达与早发AD相关的已知人类突变。越来越多的证据表明，在症状发展之前发生了细胞功能的变化在广告中。此外，基于淀粉样假说的临床药物试验缺乏成功表明更大了解广告过程对于开发新颖有效的疗法是必要的。为了解决这些问题，我们已经使用了新型的蛋白质组学技术来将新合成的蛋白质标记为非对称应用/PS1小鼠，以及暴露于广告状内存的有症状的APP/PS1小鼠定义。我们的初步研究表明蛋白质合成在这些小鼠中失调，蛋白质成分的合成显着变化甚至在症状发作之前也观察到核糖体的核糖体。因为这些发现可能是这种病理的基础蛋白质病，我们建议研究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的合成中观察到的年龄依赖性改变（RP）在淀粉样蛋白和Tau模型小鼠中改变了选择性mRNA的翻译，最终导致突触和记忆力障碍。此外，由于RP合成最近已证明在 AD和FTD样tauopathy的RTG4510小鼠模型，我们假设RP合成的改变对AD和FTD样TAU失调的反应可能会影响核糖体蛋白含量，并类似地影响翻译活动。我们首先将确定无症状的功能性核糖体的RP含量和有症状的应用程序/PS1小鼠。然后，我们将确定来自AD模型小鼠的核糖体的翻译活性。最后，我们将确定来自K3和PS19小鼠的核糖体的RP化学计量和翻译活性陶氏病和神经退行性的模型。这些实验的结果将进一步我们对神经退行性疾病过程，为AD和FTD患者细胞的类似研究铺平了道路，随后确定用于治疗AD和FTD的治疗靶标。