Determine the neurotoxicity of RNA metabolism dysfunction caused by cytoplasmic TDP-43 aggregates
Determine the neurotoxicity of RNA metabolism dysfunction caused by cytoplasmic TDP-43 aggregates
批准号:
10730167
负责人:
Sarah H Shahmoradian
金额:
$61.71万
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-09-19 至 2028-08-31
关键词:
ALS patientsAffectAlzheimer&aposs DiseaseAlzheimer&aposs disease patientAlzheimer&aposs disease related dementiaArchitectureAutopsyBrainCell membraneCellsComplexCore AssemblyCytoplasmCytoplasmic GranulesDementiaDiseaseElderlyElectron MicroscopyFrontotemporal DementiaFunctional disorderHalf-LifeHippocampusImageImmediate-Early GenesImmunohistochemistryImpairmentLiquid substanceMembraneMessenger RNAMorphologyMotor NeuronsMusMutationNamesNeurodegenerative DisordersNeuronsNonsense-Mediated DecayOrganellesPathologicPathologyPatientsPhasePhase TransitionPhysical condensationPost-Translational Protein ProcessingProcessProteinsProteomicsRNARNA ProcessingRNA metabolismRNA-Binding ProteinsReportingRibonucleoproteinsSamplingSpinal CordStressSyndromeTDP-43 aggregationTestingTissuesToxic effectTranslational Repressionage relatedin vivoinduced pluripotent stem cellinnovationlight microscopylimbic-predominant age-related TDP-43 encephalopathymRNA DecaymRNA Transcript Degradationneuronal cell bodyneuropathologyneurotoxicityprion-likeprotein TDP-43protein aggregationprotein complexresponse
中文摘要
本研究旨在确定TDP-43蛋白聚集如何失调p -体功能
英文摘要
This proposal seeks to determine how TDP-43 protein aggregates dysregulate P-body function in
neurons and subsequently produce neurotoxicity. Cytoplasmic aggregation of TDP-43 has been reported in
nearly every age-dependent neurodegenerative disease, including in >40% of frontotemporal dementia (FTD),
in the hippocampal neurons of Alzheimer’s disease (AD) patients, in >90% of ALS. It also defines a recently
recognized AD-like dementia in the oldest elderly, an AD-like syndrome named Limbic-predominant Age-
related TDP-43 Encephalopathy (LATE). We have identified that TDP-43 cytoplasmic aggregates regulate the
liquid-liquid phase separation (LLPS) of RNA processing bodies (P-bodies) in neuron-like cells and
postmortem spinal cord motor neurons in ALS patients. P-bodies are cytoplasmic membraneless
ribonucleoprotein (RNP) granules composed of RNAs and protein complexes involved in translational repression
and mRNA decay. Neurons carry a high number of P-bodies in the soma. We hypothesize that TDP-43
aggregation causes neuronal toxicity by disrupting the morphology and function of P-bodies. Our
proposal is highly innovative because how TDP-43 proteinopathy regulates the LLPS of other membraneless
organelles has not been reported in vivo. We propose to use cutting-edge imaging, proteomic, and sequencing
approaches to determine the protein and RNA composition of neuronal P-bodies and how it changes in response
to TDP-43 aggregation in vivo. We will first determine how TDP-43 cytoplasmic aggregates initiate P-body
disassembly and then determine the RNA metabolism change in neurons carrying TDP-43 aggregates or
defective P-bodies. Lastly and importantly, we will determine whether P-body proteins and RNA can serve as
pathological markers for AD-related dementia, such as LATE.
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会议论文
Cellular Anatomy of Tau Seeding
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批准号:10575918
-
项目类别:
-
资助金额:$24.6万
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财政年份:2022
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负责人:Sarah H Shahmoradian
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依托单位:
海外基金