Isoform-dependent effects of tau phosphorylation in Alzheimer's disease
阿尔茨海默病中 tau 磷酸化的异构体依赖性效应
基本信息
- 批准号:10745286
- 负责人:
- 金额:$ 7.18万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-01 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAddressAdultAffectAffinityAgeAgingAlternative SplicingAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer&aposs disease patientBehaviorBindingBiological AssayBiologyBiophysicsBrainCellsChargeChemicalsChemistryComplementDataDementiaDevelopmentDimensionsDiseaseDisease ProgressionDissociationDoctor of PhilosophyEmbryoEmbryonic DevelopmentFTD with parkinsonismFetal TissuesFluorescenceFunctional disorderFutureGoalsGrantHeterogeneityHippocampusImpairmentIn VitroInjectionsLeadLengthLinkMAPT geneMeasuresMicrotubule PolymerizationMicrotubule StabilizationMicrotubulesMolecular ConformationMusMutateMutationNerve DegenerationNeurodegenerative DisordersNeuronsNeurosciencesPathologicPathologyPatternPhosphorylationPhosphorylation SitePlayPositioning AttributeProtein BiosynthesisProtein IsoformsProteinsResearch PersonnelResolutionRoleScienceSiteSolubilitySpectrum AnalysisStructureTauopathiesTechniquesTestingTotal Internal Reflection FluorescentTrainingTransgenic MiceTubulinTubulin Interactionage relatedaging brainbiophysical techniqueschemical synthesisdriving forceexperimental studyfetalgain of functionhyperphosphorylated tauin vivoinsightmouse modelnervous system disorderneuropathologynovelpeptide chemical synthesispost-doctoral trainingproteostasissingle moleculesingle-molecule FRETskillstau Proteinstau aggregationtau functiontau mutationtau-1tool
项目摘要
Neuropathology of the microtubule-associated protein tau is central to numerous devastating neurological
disorders termed tauopathies, including Alzheimer's disease (AD). Tau promotes microtubule (MT)
polymerization and stability via its interaction with tubulin, regulated by phosphorylation to tau in multiple
domains. Six major tau isoforms are alternatively spliced in an age-dependent manner. While FTDP-17-causing
mutations in tau show isoform-dependent effects on aggregation and microtubule stabilization, there are no tau
mutations linked to AD. Meanwhile, isoform-dependent effects of phosphorylation to tau remain unexplored.
Interestingly, I discovered that numerous AD-relevant phospho-tau (pTau) sites are also phosphorylated during
normal embryonic development, and then decrease over age. Why are specific pTau sites, which are correlated
with disease, also expressed during normal development? The parallel between the developmental and
pathological states suggests that understanding the function of pTau during development would elucidate the
mechanism(s) underlying tau pathology in AD. My preliminary data indicate that i) numerous AD-relevant pTau
sites are expressed in normal embryonic mouse brains, ii) pTau is soluble and likely functional in fetal tissue, iii)
phosphorylation at sites T231, S235 and S262 impair MT polymerization by the fetal tau isoform but not an adult
isoform, and iv) these same pTau sites accelerate aggregation of the adult isoform over the fetal isoform. Recent
evidence demonstrates that tau initiates nucleation of MT polymerization. Based on my preliminary data, !
propose that tau phosphorylation has isoform-dependent effects, in which specific pTau sites are detrimental to
adult isoforms in an aging brain but functional in the fetal isoform in developing brains. I will explore two aims
which will provide critical insight to understanding the effects of tau phosphorylation in each isoform. In Aim 1, I
will determine the relationship between the interaction between pTau with both soluble tubulin and stabilized
MTs in each isoform. In Aim 2, I will test for the relationship between pTau sites which cause tau to dissociate
from MTs with those that accelerate its aggregation and/or seeding activity. Importantly, our lab has uniquely
synthesized full-length tau with genuine chemical phosphorylation at sites T231, S235 and S262 for these
studies. These experiments will be tested using multiple platforms including these chemically-synthesized
proteins, high-resolution single-molecule techniques (single-molecule FRET, fluorescence correlative
spectroscopy, and time-lapse TIRF microscopy), and injection of semi-synthesized proteins into mouse brains.
The investigator has 6+ years of expertise in working with the biological assays and mouse models described
here, and the sponsor and collaborators will guide training in the described chemical and biophysical techniques.
I anticipate that my findings will elucidate the function of tau in developing neurons, and will provide insight into
mechanisms of pathological tau hyperphosphorylation across numerous tauopathies including AD.
微管相关蛋白tau的神经病理学是许多毁灭性神经系统疾病的核心
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)
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Nima Nick Naseri其他文献
Nima Nick Naseri的其他文献
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{{ truncateString('Nima Nick Naseri', 18)}}的其他基金
Isoform-dependent effects of tau phosphorylation in Alzheimer's disease
阿尔茨海默病中 tau 磷酸化的异构体依赖性效应
- 批准号:
10536450 - 财政年份:2022
- 资助金额:
$ 7.18万 - 项目类别:
Disease causing mutations in cysteine string protein-alpha disrupt SNARE-dependent lysosomal exocytosis
导致疾病的半胱氨酸串蛋白-α 突变破坏 SNARE 依赖性溶酶体胞吐作用
- 批准号:
9326766 - 财政年份:2017
- 资助金额:
$ 7.18万 - 项目类别:
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