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:
- 金额:$ 43.59万
- 依托单位:
- 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:
- 关键词:5&apos Untranslated RegionsAPP-PS1AblationAddressAffectAgeAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAmyloidAppearanceCell physiologyCellsChronicClinicalCluster AnalysisDevelopmentDiseaseDrosophila genusExhibitsFrontotemporal DementiaFunctional disorderGeneticGenetic TranslationGenotypeHippocampus (Brain)HumanImpairmentInvestigationLabelMemoryMemory LossMemory impairmentMessenger RNAModelingMusMutant Strains MiceMutationNerve DegenerationNeurodegenerative DisordersNeurofibrillary TanglesOpen Reading FramesPathologicPathologyPathway interactionsPatientsPharmaceutical PreparationsPharmacologyPhosphorylationPhosphotransferasesPresenile Alzheimer DementiaPrion DiseasesProcessProtein BiosynthesisProteinsProteomeProteomicsRegulationRibosomal ProteinsRibosomesSenile PlaquesSliceSpecificitySubgroupSymptomsSynapsesSynaptic plasticityTauopathiesTechnologyTestingTimeTissuesTranslatingTranslation InitiationTranslationsWorkadvanced diseaseage relatedbaseeffective therapyembryonic stem cellexperimental studyhyperphosphorylated tauimprovedinsightlong term memorymouse modelnovelnovel therapeuticspreventprotein functionproteostasisresponsestoichiometrysuccesstau Proteinstau dysfunctiontherapeutic 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.
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性核糖体的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。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Eric Klann其他文献
Eric Klann的其他文献
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{{ truncateString('Eric Klann', 18)}}的其他基金
Translational Control in Memory and Brain Disorders
记忆和大脑疾病的翻译控制
- 批准号:
10399633 - 财政年份:2021
- 资助金额:
$ 43.59万 - 项目类别:
Translational Control in Memory and Brain Disorders
记忆和大脑疾病的翻译控制
- 批准号:
10613505 - 财政年份:2021
- 资助金额:
$ 43.59万 - 项目类别:
Translational Control in Memory and Brain Disorders
记忆和大脑疾病的翻译控制
- 批准号:
10239794 - 财政年份:2021
- 资助金额:
$ 43.59万 - 项目类别:
Targeting Mitochondrial Superoxide in Angelman Syndrome
靶向天使综合征中的线粒体超氧化物
- 批准号:
8337857 - 财政年份:2011
- 资助金额:
$ 43.59万 - 项目类别:
Targeting Mitochondrial Superoxide in Angelman Syndrome
靶向天使综合征中的线粒体超氧化物
- 批准号:
8289784 - 财政年份:2011
- 资助金额:
$ 43.59万 - 项目类别:
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