Poly(ADP-ribose)-dependent TDP-43 pathology in oxidative stress (R21)
氧化应激中聚 (ADP-核糖) 依赖性 TDP-43 病理学 (R21)
基本信息
- 批准号:10753095
- 负责人:
- 金额:$ 40.84万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-01 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAddressAffectAlzheimer&aposs DiseaseAlzheimer&aposs disease related dementiaAmyotrophic Lateral SclerosisAreaBindingBiochemicalBiologicalBiological AssayCell DeathCell NucleusCellsCessation of lifeCryoelectron MicroscopyCytoplasmCytosolDNA-Binding ProteinsDataDefectDementiaDeuteriumDiseaseEventExposure toFrontotemporal DementiaHydrogenHydrogen PeroxideImaging TechniquesImpairmentInclusion BodiesLengthLigationLimbic SystemMass Spectrum AnalysisMediatingModelingMolecular ConformationMusMutationNatureNeurodegenerative DisordersNeuronsNuclearNuclear ExportNuclear ImportNuclear Localization SignalNuclear ProteinOxidative StressOxidative Stress InductionPathologicPathologic ProcessesPathologyPathway interactionsPhysiologicalPlayPoly Adenosine Diphosphate RibosePoly(ADP-ribose) Polymerase InhibitorPoly(ADP-ribose) PolymerasesPolymersPropertyProtein Export PathwayProtein translocationProteinsPublishingRNA Recognition MotifRoleSignal TransductionSignaling MoleculeSolubilityStressStructureTemporal LobeTimeToxic effectTransactivationVariantbiophysical propertiesconfocal imagingconformational alterationdisease-causing mutationexportin 1 proteininhibitornervous system disorderneuron lossprotein TDP-43responsevirtual
项目摘要
Abstract
Frontotemporal dementia (FTD) is an Alzheimer-related dementia disease (ADRD) and involves nuclear
egress and cytoplasmic Transactivation response DNA binding protein 43 (TDP-43). The mechanisms for
pathological export of TDP-43 or its accumulation in the cytoplasm is not clearly defined. Although, studies
on disease-causing mutations have revealed that defects in nuclear import may be in part responsible for
TDP-43 accumulation in the cytosol as these mutations change the properties of the protein. However, it
remains largely unclear how TDP-43 accumulates in the cytosol, as the majority of the TDP-43 dependent
pathologies are sporadic. TDP-43 contains two RNA recognition motifs (RRMs), a nuclear export signal
(NES), and a nuclear localization signal (NLS) in its N-terminus, and binds poly (ADP-ribose) polymer (PAR)
via a PAR-binding motif embedded in its NLS. Studies have shown that PAR inhibitors can inhibit TDP-43
pathology, and binding of PAR to TDP-43 can change its biophysical characteristics in solution. Exportin 1
(XPO1) mediates the NES-dependent export of proteins from the nucleus. TDP-43 is a 43kDa protein that
may not require XPO1-dependent export under basal conditions but our data indicates that under neuronal
stress conditions TDP-43 egresses the nucleus via XPO-1 dependent export. We hypothesize that in disease
conditions like FTD type ADRD and related diseases; PAR binds TDP-43 in the nucleus and facilitates its
interaction with XPO-1, which subsequently enhances the egress of TDP-43 from the nucleus to cytosol.
This proposal is supported our preliminary data that both PARP inhibitor BMN673 and XPO-1 inhibitor KPT-
185 inhibit the cytosolic accumulation of TDP-43 in neurons and TDP-43 and XPO1 interact following PARP
activation. In this proposal, we plan to study the alterations in TDP-43 in mouse cortical neurons exposed to
oxidative stress. Oxidative stress is a common pathological process mediating protein mislocalization,
aggregation, and cell death in virtually all neurological disorders including FTD. Oxidative stress via H2O2 in
cortical neurons mediates a robust TDP-43 cytosolic localization. Therefore, it is likely that pathophysiological
mechanisms identified in the oxidative stress model in cortical neurons can closely overlap/mimic pathological
mechanisms in FTD and other ADRD involving changes/mislocalization of TDP-43.
We will use biochemical, cell biological and imaging techniques in combination with proximity ligation assays,
CryoEM, and Hydrogen/Deuterium Exchange mass spectrometry to assess the PAR-dependent alteration in
TDP-43 and its interaction with XPO-1 that leads to an increase in the release of TDP-43 from the nucleus
and subsequent accumulation/aggregation in the cytoplasm. These studies will help in understanding the
pathophysiological mechanisms of TDP-43 accumulation in FTD, ALS, and other ADRD/dementia related
diseases involving TDP-43
摘要
额颞叶痴呆(FTD)是一种阿尔茨海默病相关的痴呆症(ADRD),
出口和细胞质反式激活反应DNA结合蛋白43(TDP-43)。的机制
TDP-43的病理性输出或其在细胞质中的积累并不清楚。虽然,研究
关于致病突变的研究表明,核输入的缺陷可能是导致
TDP-43在胞质溶胶中积累,因为这些突变改变了蛋白质的性质。但
TDP-43如何在胞质溶胶中积累仍然很不清楚,因为大多数依赖TDP-43的
病理是偶发的。TDP-43含有两个RNA识别基序(RRM),即核输出信号
(NES)和核定位信号(NLS)在其N-末端,并结合聚(ADP-核糖)聚合物(PAR)
通过其NLS中嵌入的PAR结合基序。研究表明,PAR抑制剂可以抑制TDP-43
PAR与TDP-43的结合可以改变其在溶液中的生物物理特性。输出1
(XPO 1)介导NES依赖的蛋白质从细胞核输出。TDP-43是一种43 kDa的蛋白质,
在基础条件下可能不需要依赖XPO 1的输出,但我们的数据表明,在神经元条件下,
应激条件下TDP-43通过XPO-1依赖性输出而从细胞核中排出。我们假设在疾病中
如FTD型ADRD和相关疾病; PAR在细胞核中结合TDP-43,
与XPO-1的相互作用,其随后增强TDP-43从细胞核到胞质溶胶的流出。
这一提议得到了我们的初步数据的支持,即PARP抑制剂BMN 673和XPO-1抑制剂KPT-1都是PARP抑制剂。
185抑制TDP-43在神经元中的胞质蓄积,并且TDP-43和XPO 1在PARP后相互作用
activation.在这个提议中,我们计划研究暴露于以下物质的小鼠皮层神经元中TDP-43的改变:
氧化应激氧化应激是介导蛋白质错误定位的常见病理过程,
在几乎所有神经系统疾病(包括FTD)中的聚集和细胞死亡。通过H2 O2的氧化应激,
皮质神经元介导了稳健的TDP-43胞质定位。因此,很可能病理生理学
在皮质神经元中的氧化应激模型中鉴定的机制可以紧密重叠/模拟病理学
涉及TDP-43变化/错误定位的FTD和其他ADRD机制。
我们将使用生物化学,细胞生物学和成像技术与邻近连接试验相结合,
CryoEM和氢/氘交换质谱,以评估PAR依赖性改变,
TDP-43及其与XPO-1的相互作用导致TDP-43从细胞核释放增加
以及随后在细胞质中的积累/聚集。这些研究将有助于了解
FTD、ALS和其他ADRD/痴呆相关疾病中TDP-43蓄积的病理生理学机制
TDP-43相关疾病
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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Shaida A. Andrabi其他文献
The AAA + ATPase Thorase is neuroprotective against ischemic injury.
AAA--ATPase Thorase 具有针对缺血性损伤的神经保护作用。
- DOI:
10.1177/0271678x18769770 - 发表时间:
2018 - 期刊:
- 影响因子:6.3
- 作者:
Jianmin Zhang;Jia Yang;Huaishan Wang;Omar Sherbini;Matthew J. Keuss;George K. E. Umanah;Emily Ling-Lin Pai;Zhikai Chi;Kaisa M. A. Paldanius;Wei He;Hong Wang;Shaida A. Andrabi;Ted M. Dawson;Valina L. Dawson - 通讯作者:
Valina L. Dawson
The AAA + ATPase Thorase is neuroprotective against ischemic injury.
- DOI:
doi: 10.1177/0271678X18769770 - 发表时间:
2018 - 期刊:
- 影响因子:
- 作者:
Jianmin Zhang;Jia Yang;Huaishan Wang;Omar Sherbini;Matthew J. Keuss;George K. E. Umanah;Emily Ling-Lin Pai;Zhikai Chi;Kaisa M. A. Paldanius;Wei He;Hong Wang;Shaida A. Andrabi;Ted M. Dawson;Valina L. Dawson - 通讯作者:
Valina L. Dawson
HIF1α-regulated glycolysis promotes activation-induced cell death and IFN-γ induction in hypoxic T cells
HIF1α 调节的糖酵解促进缺氧 T 细胞中激活诱导的细胞死亡和 IFN-γ 诱导
- DOI:
10.1038/s41467-024-53593-8 - 发表时间:
2024-10-30 - 期刊:
- 影响因子:15.700
- 作者:
Hongxing Shen;Oluwagbemiga A. Ojo;Haitao Ding;Logan J. Mullen;Chuan Xing;M. Iqbal Hossain;Abdelrahman Yassin;Vivian Y. Shi;Zach Lewis;Ewa Podgorska;Shaida A. Andrabi;Maciek R. Antoniewicz;James A. Bonner;Lewis Zhichang Shi - 通讯作者:
Lewis Zhichang Shi
Shaida A. Andrabi的其他文献
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{{ truncateString('Shaida A. Andrabi', 18)}}的其他基金
SULT4a1, a novel neuroprotective protein in stroke
SULT4a1,一种新型中风神经保护蛋白
- 批准号:
10308473 - 财政年份:2020
- 资助金额:
$ 40.84万 - 项目类别:
SULT4a1, a novel neuroprotective protein in stroke
SULT4a1,一种新型中风神经保护蛋白
- 批准号:
10527352 - 财政年份:2020
- 资助金额:
$ 40.84万 - 项目类别:
SULT4a1, a novel neuroprotective protein in stroke
SULT4a1,一种新型中风神经保护蛋白
- 批准号:
10096888 - 财政年份:2020
- 资助金额:
$ 40.84万 - 项目类别:
Poly (ADP-ribose) Mediates Cell Death in Stroke by Inhibiting Glucose Metabolism
聚(ADP-核糖)通过抑制葡萄糖代谢介导中风细胞死亡
- 批准号:
9261611 - 财政年份:2015
- 资助金额:
$ 40.84万 - 项目类别:
Poly (ADP-ribose) Mediates Cell Death in Stroke by Inhibiting Glucose Metabolism
聚(ADP-核糖)通过抑制葡萄糖代谢介导中风细胞死亡
- 批准号:
8962711 - 财政年份:2015
- 资助金额:
$ 40.84万 - 项目类别:
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