Tau Post-Translational Modifications and Mitochondrial Quality Control
Tau 翻译后修饰和线粒体质量控制
基本信息
- 批准号:10188394
- 负责人:
- 金额:$ 57.09万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-06-15 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:AblationAcetylationAddressAffectAgeAge of OnsetAgingAlzheimer&aposs DiseaseAlzheimer&aposs disease brainAnimal ModelAttenuatedAuxinsBehavioralBiologyBiosensorBuffersCRISPR/Cas technologyCaenorhabditis elegansCellsCollaborationsDataDiseaseDisease ProgressionDisease modelEpitopesExhibitsFoundationsGenesGeneticGenetic ModelsGenetic TranscriptionGenomicsHealthHomeostasisImpairmentInterventionKnowledgeLentivirusMeasuresMediator of activation proteinMetabolicMitochondriaModelingMolecularMusMutationNematodaNerve DegenerationNeurodegenerative DisordersNeuronal DysfunctionNeuronsNuclearOrganellesOutputOxidative StressPathogenesisPathologicPathway interactionsPhenotypePhosphorylationPhysiologicalPlayPost-Translational Protein ProcessingProcessProteinsQuality ControlResourcesRoleSeveritiesSignal PathwaySignal TransductionSiteStressStructureSystemTauopathiesTestingTherapeuticTimeToxic effectTransgenic ModelTransgenic OrganismsTranslatingUbiquitinage relatedage related neurodegenerationbiological adaptation to stresscomparativediet and exerciseearly onsetfunctional declinegenetic resourcehealthy agingimaging approachinsightmitochondrial dysfunctionmutantneuron lossneurotoxicitynoveloptogeneticsoverexpressionproteostasisproteotoxicityreceptorresponsestemtau Proteinstau aggregationtau expressiontau functiontau mutationtau phosphorylation
项目摘要
Tau is a central player in the pathogenesis of numerous age-related neurodegenerative diseases,
with Alzheimer’s disease (AD) being the best example. Tau from AD brain is defined by aberrant
posttranslational modifications (PTMs), including increases in phosphorylation and acetylation at
specific epitopes. The UNDERLYING PREMISE of this proposal is that specific, disease relevant PTMs
impair tau function which negatively impacts neuronal health. While the formation of insoluble fibrillary
structures is influenced by PTMs, data strongly indicate that soluble forms of abnormally modified tau are
the mediators of neuronal toxicity. There are data indicating that overexpression of AD-relevant forms of
tau results in increased levels of fragmented, dysfunctional mitochondria, which may be due to in part
due to impaired mitophagy, as well as other perturbations of mitochondrial quality control (MQC)
mechanisms. However, a CRITICAL KNOWLEDGE GAP is how these modified tau species, when
present at physiologically relevant levels, influence mitochondrial and neuronal health. The OVERALL
HYPOTHESIS of this proposal is that tau with AD-relevant PTMs exerts toxic effects through impairing MQC
mechanisms. An impaired ability to resolve mitochondrial stress would increase the presence of less
functional mitochondria with a concomitant increase in oxidative stress and neuronal dysfunction. The
overall result would be an earlier onset of an aged neuron phenotype. The NOVELTY of this project stems
in part from its use of single-copy transgenic tau models that avoid overexpression, as well as the
inclusion of age as a variable in a genetic model organism. The nematode C. elegans benefits
from a vast repertoire of genetic, transgenic and genomic resources that will be leveraged to investigate the
molecular underpinnings of AD and to define the precise mechanism through which tau PTMs
compromise mitochondrial function and accelerate neuronal aging. Our preliminary data support this
approach as worms with single copy expression of tau with specific AD-relevant PTMs in
mechanosensory neurons show a significant increase in age-dependent neurodegeneration and a suppression
of stress-induced mitophagy. These and other preliminary data provide a strong foundation for the studies
in this application. The aims of this proposal are: (1) To determine the impact of AD relevant tau PTMs
on mitochondrial stress responses and how this influences healthy aging of neurons, (2) To test the
hypothesis that tau with AD relevant PTMs impairs mitochondrial dynamics and mitophagy, and (3) To
address whether enhancing MQC is a viable therapeutic avenue. The relative contribution of these responses
to neuronal age-dependent deficits will be tested using unique genetic resources available in worms. The
IMPACT of these studies will be to provide crucial new insights into the mechanisms by which
pathological tau species compromise mitochondrial function and neuronal health.
Tau在许多与年龄相关的神经退行性疾病的发病机制中发挥着核心作用,
阿尔茨海默病(AD)就是最好的例子。来自阿尔茨海默病大脑的tau被定义为异常
翻译后修饰(PTM),包括增加磷酸和乙酰化
特定的表位。这项提议的基本前提是特定的、与疾病相关的PTM
损害tau功能,从而对神经元健康产生负面影响。而不溶于水的纤维的形成
结构受到PTMS的影响,数据强烈表明,可溶形式的异常修饰的tau是
神经毒性的中介物。有数据表明,AD相关形式的过度表达
Tau导致线粒体碎裂和功能障碍的水平增加,这可能是部分原因
由于线粒体吞噬功能受损,以及线粒体质量控制(MQC)的其他干扰
机制。然而,一个关键的知识缺口是这些修饰的tau物种是如何
存在于生理相关水平,影响线粒体和神经元的健康。整体而言
该方案的假设是,伴有AD相关PTMS的tau通过损害MQC而发挥毒性作用
机制。解决线粒体压力的能力受损会增加更少的
功能线粒体伴随氧化应激和神经元功能障碍的增加。这个
总体结果将是衰老神经元表型的发病时间更早。这个项目的新颖性源于
部分原因是它使用了避免过度表达的单拷贝转基因tau模型,以及
将年龄作为一个变量包含在遗传模式生物中。线虫对线虫的好处
来自大量的遗传、转基因和基因组资源,这些资源将被用来研究
AD的分子基础,并定义tau PTM的确切机制
损害线粒体功能,加速神经元衰老。我们的初步数据支持这一点
作为带有特定AD相关PTM的tau单拷贝表达的蠕虫
机械感觉神经元显示年龄依赖性神经变性和抑制显著增加。
应激诱导的有丝分裂。这些和其他初步数据为研究提供了坚实的基础
在此应用程序中。本提案的目的是:(1)确定与AD相关的tau PTMS的影响
关于线粒体应激反应以及这如何影响神经元的健康老化,(2)测试
假设tau与AD相关的PTMS损害线粒体动力学和有丝分裂,以及(3)
解决加强MQC是否是可行的治疗途径。这些回应的相对贡献
将使用蠕虫中可用的独特遗传资源来测试与神经元年龄相关的缺陷。这个
这些研究的影响将是为以下机制提供至关重要的新见解:
病理性tau损害线粒体功能和神经元健康。
项目成果
期刊论文数量(0)
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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Gail V. W. Johnson其他文献
Glycogen Synthase Kinase 3β Phosphorylates Tau at Both Primed and Unprimed Sites
糖原合酶激酶 3β 在引发和未引发的位点磷酸化 Tau
- DOI:
- 发表时间:
2003 - 期刊:
- 影响因子:4.8
- 作者:
Jae;Gail V. W. Johnson - 通讯作者:
Gail V. W. Johnson
Metal-catalyzed oxidation of bovine neurofilaments in vitro.
牛神经丝的体外金属催化氧化。
- DOI:
- 发表时间:
1995 - 期刊:
- 影响因子:7.4
- 作者:
Juan C. Troncoso;Anthony C. Costello;James H. Kim;Gail V. W. Johnson - 通讯作者:
Gail V. W. Johnson
Gail V. W. Johnson的其他文献
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{{ truncateString('Gail V. W. Johnson', 18)}}的其他基金
Mitochondrial dysfunction and tau pathology in Alzheimer's disease
阿尔茨海默病中的线粒体功能障碍和 tau 病理学
- 批准号:
10805120 - 财政年份:2023
- 资助金额:
$ 57.09万 - 项目类别:
Mechanisms of Transglutaminase 2 (TG2)-Mediated Gene Expression in Astrocyte
星形胶质细胞中转谷氨酰胺酶 2 (TG2) 介导的基因表达机制
- 批准号:
10293984 - 财政年份:2021
- 资助金额:
$ 57.09万 - 项目类别:
BAG3 regulates Rab35 and the ESCRT/endolysosome pathway
BAG3 调节 Rab35 和 ESCRT/内溶酶体途径
- 批准号:
10269305 - 财政年份:2021
- 资助金额:
$ 57.09万 - 项目类别:
BAG3 regulates Rab35 and the ESCRT/endolysosome pathway
BAG3 调节 Rab35 和 ESCRT/内溶酶体途径
- 批准号:
10461933 - 财政年份:2021
- 资助金额:
$ 57.09万 - 项目类别:
BAG3 regulates Rab35 and the ESCRT/endolysosome pathway
BAG3 调节 Rab35 和 ESCRT/内溶酶体途径
- 批准号:
10667539 - 财政年份:2021
- 资助金额:
$ 57.09万 - 项目类别:
Tau Post-Translational Modifications and Mitochondrial Quality Control
Tau 翻译后修饰和线粒体质量控制
- 批准号:
10374933 - 财政年份:2020
- 资助金额:
$ 57.09万 - 项目类别:
Tau Post-Translational Modifications and Mitochondrial Quality Control
Tau 翻译后修饰和线粒体质量控制
- 批准号:
10601125 - 财政年份:2020
- 资助金额:
$ 57.09万 - 项目类别:
Tau protein turnover and mitochondrial stress responses
Tau 蛋白周转和线粒体应激反应
- 批准号:
9761421 - 财政年份:2018
- 资助金额:
$ 57.09万 - 项目类别:
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