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:10601125
- 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:AblationAccelerationAcetylationAddressAffectAgeAge of OnsetAgingAlzheimer&aposs DiseaseAlzheimer&aposs disease brainAttenuatedAuxinsBehavioralBiologyBiosensorBuffersCRISPR/Cas technologyCaenorhabditis elegansCellsCollaborationsDataDedicationsDietDiseaseDisease ProgressionDisease modelEpitopesExerciseExhibitsFoundationsGenesGeneticGenetic ModelsGenetic TranscriptionHealthHomeostasisImpairmentInterventionKnowledgeLentivirusMeasuresMediatorMetabolicMitochondriaModelingMolecularMusMutationNematodaNerve DegenerationNeurodegenerative DisordersNeuronal DysfunctionNeuronsNuclearOrganellesOutputOxidative StressPathogenesisPathologicPathway interactionsPhenotypePhosphorylationPhysiologicalPlayPost-Translational Protein ProcessingProcessProteinsQuality ControlRoleSeveritiesSignal PathwaySignal TransductionSiteStressStructureSystemTauopathiesTestingTherapeuticTimeToxic effectTransgenic ModelTransgenic OrganismsTranslatingUbiquitinage relatedage related neurodegenerationbiological adaptation to stresscomparativeearly onsetfunctional declinegenetic resourcegenome resourcehealthy agingimaging approachinsightmimeticsmitochondrial dysfunctionmodel organismmutantneuron lossneurotoxicitynoveloptogeneticsoverexpressionproteostasisproteotoxicityreceptorresponsestemtau Proteinstau aggregationtau expressiontau functiontau mutationtau-1translational potential
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蛋白在许多与年龄相关的神经退行性疾病的发病机制中起着核心作用,
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:
10188394 - 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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