Elucidating The Aberrant TDP-43 Species That Promote Neurodegeneration
Elucidating The Aberrant TDP-43 Species That Promote Neurodegeneration
批准号:
10385722
负责人:
Todd Jonathan Cohen
金额:
$34.02万
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-06-15 至 2023-03-31
关键词:
ALS patientsAcetylationAlzheimer&aposs DiseaseAutomobile DrivingBehaviorBehavioralBiochemicalCell NucleusCessation of lifeClinicalClustered Regularly Interspaced Short Palindromic RepeatsCognition DisordersCognitive deficitsDataDefectDetectionDiseaseDisease ProgressionDissociationEventFunctional disorderFutureGene Expression ProfileGenetic TranscriptionGoalsHSF1HistologyHumanImpairmentIndividualKnock-in MouseLightLinkLysineMessenger RNAModelingModificationMolecular ChaperonesMotor NeuronsMusMutant Strains MiceMutationNerve DegenerationNeurodegenerative DisordersNeurologicNeuronsNuclearOnset of illnessPathogenesisPathogenicityPathologicPathologyPhysiologicalRNA Recognition MotifRoleSignal TransductionSymptomsSyndromeTestingTherapeuticToxic effectapproach behaviorbaseeffective therapyfrontotemporal lobar dementia-amyotrophic lateral sclerosisgain of functionhuman diseasein vivoin vivo evaluationinnovationinsightmotor deficitmotor disordermouse modelneurodegenerative phenotypeneuron losspreventprotein TDP-43proteostasisresponsetherapeutic targettranscription factortranscriptometranscriptome sequencingtreatment strategy
中文摘要
TDP-43功能障碍是一系列神经退行性疾病的基础,统称为TDP-43
蛋白质病,以神经元丢失、行为异常和最终死亡为特征。
令人惊讶的是,人们对TDP-43如何经历如此戏剧性的转变而引发疾病知之甚少。
进步。最近,我们发现TDP-43受到可逆的赖氨酸乙酰化的影响,这是一种修饰
在TDP-43‘S的RNA结合区内,有显著的作用;它使TDP-43与其靶标解离
并加速TDP-43‘S的聚集倾向。事实上,乙酰化的TDP-43包裹体是
在肌萎缩侧索硬化症(ALS)患者的运动神经元中检测到,这表明这一异常的作用
TDP-43修饰形式在疾病发病机制中的作用我们利用这一有趣的发现产生了第一个
基于CRISPR的非转基因TDP-43小鼠模型含有类似乙酰化的突变,因此
制作与生理相关的TDP-43蛋白病变模型。我们假设TDP-43
乙酰化会导致神经退化和疾病进展,现在可以直接在
活着。我们的初步数据已经显示出TDP-43病理、核TDP-43清除以及
突变小鼠的显著行为缺陷。在AIM-1中,我们将使用组织学、生化和行为学
全面描述神经退行性变表型的方法。在AIM-2中,我们阐明了治疗
激活主转录因子HSF1或特定下游伴侣蛋白的潜力,以诱导
高度协调的转录级联能够抑制乙酰化的TDP-43功能障碍和
恢复核TDP-43水平。最后,在AIM-3中,我们将揭示早期阶段的扰动
发生于乙酰化的TDP-43的转录组,但出现在明显的神经变性和
行为缺陷。我们的建议意义重大,因为它将突出TDP-43的异常形式是一种看似合理的
治疗目标,它将确定特定的伴侣反应作为新的途径来为神经元解毒,它将
阐明转录失调是与神经退行性变相关的关键病理机制。我们的
该提案也是创新的,因为我们将阐明异常的TDP-43修改是
疾病的发生或发展。
英文摘要
TDP-43 dysfunction underlies a spectrum of neurodegenerative diseases collectively known as TDP-43
proteinopathies, which are characterized by neuronal loss, behavioral abnormalities, and ultimately death.
Surprisingly, little is known about how TDP-43 undergoes such a dramatic transformation that initiates disease
progression. Recently, we discovered that TDP-43 is subject to reversible lysine acetylation, a modification
within TDP-43’s RNA-binding domain that has a remarkable effect; it disengages TDP-43 from its target
mRNAs and accelerates TDP-43’s propensity to aggregate. Indeed, acetylated TDP-43 inclusions were
detected in motor neurons of amyotrophic lateral sclerosis (ALS) patients, suggesting a role for this aberrantly
modified form of TDP-43 in disease pathogenesis. We leveraged this intriguing finding to generate the first
CRISPR-based, non-transgenic TDP-43 mouse model containing an acetylation-mimicking mutation, thus
producing a physiologically relevant model of TDP-43 proteinopathy. We hypothesize that TDP-43
acetylation drives neurodegeneration and disease progression, which can now be directly tested in
vivo. Our preliminary data already show evidence of TDP-43 pathology, nuclear TDP-43 clearing, and
prominent behavioral defects in mutant mice. In Aim-1, we will use histology, biochemical, and behavior
approaches to fully characterize the neurodegenerative phenotype. In Aim-2, we shed light on the therapeutic
potential of activating the master transcription factor HSF1, or specific downstream chaperones, to induce a
highly coordinated transcriptional cascade capable of suppressing acetylated TDP-43 dysfunction and
restoring nuclear TDP-43 levels. Finally, in Aim-3, we will uncover early-stage perturbations in the
transcriptome that occur in response to acetylated TDP-43, but emerge prior to overt neurodegeneration and
behavioral defects. Our proposal is significant since it will highlight an aberrant form of TDP-43 as a plausible
therapeutic target, it will pinpoint specific chaperone responses as new avenues to detoxify neurons, and it will
illuminate transcriptional dysregulation as a critical pathomechanism associated with neurodegeneration. Our
proposal is also innovative since we will shed light on aberrant TDP-43 modifications as plausible triggers for
disease onset or progression.
期刊论文(2)
专著(0)
科研奖励(0)
会议论文
DOI:
10.1016/j.isci.2023.106645
发表时间:
2023-05-19
期刊:
ISCIENCE
影响因子:
5.8
作者:
[Evangelista, Baggio A., Cahalan, Shannon R., Ragusa, Joey V., Mordant, Angie, Necarsulmer, Julie C., Perna, Robert J., Ajit, Tejazaditya, White, Kristen, Barker, Natalie K., Tian, Xu, Cohen, Sarah, Meeker, Rick, Herring, Laura E., Cohen, Todd J.]
通讯作者:
Cohen, Todd J.
Identifying kinase signaling pathways linked to tau-mediated neurodegeneration
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批准号:10753257
-
项目类别:
-
资助金额:$25.13万
-
财政年份:2023
-
负责人:Todd Jonathan Cohen
-
依托单位:
CRISPR gene therapies targeting tau in Alzheimer's disease and tauopathies
-
批准号:10752745
-
项目类别:
-
资助金额:$42.41万
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财政年份:2023
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负责人:Todd Jonathan Cohen
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依托单位:
Sleep-dependent synaptic homeostasis in Alzheimer's disease
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批准号:10209327
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项目类别:
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资助金额:$210.65万
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财政年份:2021
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负责人:Todd Jonathan Cohen
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依托单位:
Identifying Alzheimer’s Disease Causal Variants and Target Genes Using iPSC-derived Microglia
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批准号:10382389
-
项目类别:
-
资助金额:$73.88万
-
财政年份:2020
-
负责人:Todd Jonathan Cohen
-
依托单位:
Identifying Alzheimer’s Disease Causal Variants and Target Genes Using iPSC-derived Microglia
-
批准号:10615602
-
项目类别:
-
资助金额:$72.23万
-
财政年份:2020
-
负责人:Todd Jonathan Cohen
-
依托单位:
Dual CHIP Functions Control Tau Triage In Alzheimer's Disease
-
批准号:10088361
-
项目类别:
-
资助金额:$61.97万
-
财政年份:2019
-
负责人:Todd Jonathan Cohen
-
依托单位:
Dual CHIP Functions Control Tau Triage In Alzheimer's Disease
-
批准号:10319914
-
项目类别:
-
资助金额:$61.97万
-
财政年份:2019
-
负责人:Todd Jonathan Cohen
-
依托单位:
Dual CHIP Functions Control Tau Triage In Alzheimer's Disease
-
批准号:10539271
-
项目类别:
-
资助金额:$61.97万
-
财政年份:2019
-
负责人:Todd Jonathan Cohen
-
依托单位:
TDP-43 acetylation as a pathogenic modification in ALS & related proteinopathies
-
批准号:8849550
-
项目类别:
-
资助金额:$24.9万
-
财政年份:2014
-
负责人:Todd Jonathan Cohen
-
依托单位:
TDP-43 acetylation as a pathogenic modification in ALS & related proteinopathies
-
批准号:8862550
-
项目类别:
-
资助金额:$24.36万
-
财政年份:2014
-
负责人:Todd Jonathan Cohen
-
依托单位:
TDP-43 acetylation as a pathogenic modification in ALS & related proteinopathies
-
批准号:8425349
-
项目类别:
-
资助金额:$7.44万
-
财政年份:2012
-
负责人:Todd Jonathan Cohen
-
依托单位:
TDP-43 acetylation as a pathogenic modification in ALS & related proteinopathies
-
批准号:8550549
-
项目类别:
-
资助金额:$7.44万
-
财政年份:2012
-
负责人:Todd Jonathan Cohen
-
依托单位:
海外基金