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:
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
抽象的
额颞痴呆(FTD)是阿尔茨海默氏症相关痴呆症(ADRD),涉及核
出口和细胞质反式反应反应DNA结合蛋白43(TDP-43)。机制
TDP-43的病理出口或其在细胞质中的积累尚未明确定义。虽然,研究
关于引起疾病的突变表明,核进口缺陷可能部分是为了
当这些突变改变蛋白质的特性时,TDP-43在细胞质中积累。但是,它
仍然不清楚TDP-43如何在细胞质中积聚,因为大多数TDP-43依赖
病理是零星的。 TDP-43包含两个RNA识别基序(RRMS),一个核输出信号
(NES)和其N末端中的核定位信号(NLS),并结合聚(ADP-核糖)聚合物(PAR)
通过嵌入其NLS中的Par结合基序。研究表明,PAR抑制剂可以抑制TDP-43
PAR与TDP-43与TDP-43的结合可以改变其在溶液中的生物物理特征。导出1
(XPO1)介导了核中NES依赖性蛋白的导出。 TDP-43是一种43KDA蛋白
在基础条件下可能不需要XPO1依赖性导出,但我们的数据表明在神经元下
应力条件TDP-43通过XPO-1依赖性输出来排出核。我们假设在疾病中
诸如FTD类型ADRD和相关疾病之类的疾病; PAR在细胞核中结合TDP-43并促进其
与XPO-1的相互作用,随后增强了TDP-43从细胞核到细胞质的出口。
该建议得到了我们的初步数据,即PARP抑制剂BMN673和XPO-1抑制剂KPT-
185抑制神经元中TDP-43的胞质积累,TDP-43和XPO1在PARP之后相互作用
激活。在此提案中,我们计划研究暴露于小鼠皮质神经元中TDP-43的改变
氧化应激。氧化应激是介导蛋白质错误的常见病理过程,
几乎所有神经系统疾病(包括FTD)的聚集和细胞死亡。通过H2O2氧化应激
皮质神经元介导了强大的TDP-43胞质定位。因此,病理生理可能
皮质神经元中氧化应激模型中鉴定出的机制可以紧密重叠/模拟病理
FTD和其他ADRD的机制,涉及TDP-43的变化/错误定位。
我们将使用生化,细胞生物学和成像技术与接近连接分析结合使用,
冷冻和氢/氘交换质谱法,以评估依赖性的变化
TDP-43及其与XPO-1的相互作用导致TDP-43从核中释放的增加
并随后在细胞质中积累/聚集。这些研究将有助于理解
FTD,ALS和其他ADRD/痴呆相关的TDP-43积累的病理生理机制
涉及TDP-43的疾病
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)

暂无数据
数据更新时间:2024-06-01
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:10.1177/0271678x1876977010.1177/0271678x18769770
- 发表时间:20182018
- 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. DawsonJianmin 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. DawsonValina L. Dawson
共 1 条
- 1
Shaida A. Andrabi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:1030847310308473
- 财政年份:2020
- 资助金额:$ 40.84万$ 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:1052735210527352
- 财政年份:2020
- 资助金额:$ 40.84万$ 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:1009688810096888
- 财政年份:2020
- 资助金额:$ 40.84万$ 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:92616119261611
- 财政年份:2015
- 资助金额:$ 40.84万$ 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:89627118962711
- 财政年份:2015
- 资助金额:$ 40.84万$ 40.84万
- 项目类别:
相似国自然基金
时空序列驱动的神经形态视觉目标识别算法研究
- 批准号:61906126
- 批准年份:2019
- 资助金额:24.0 万元
- 项目类别:青年科学基金项目
本体驱动的地址数据空间语义建模与地址匹配方法
- 批准号:41901325
- 批准年份:2019
- 资助金额:22.0 万元
- 项目类别:青年科学基金项目
大容量固态硬盘地址映射表优化设计与访存优化研究
- 批准号:61802133
- 批准年份:2018
- 资助金额:23.0 万元
- 项目类别:青年科学基金项目
IP地址驱动的多径路由及流量传输控制研究
- 批准号:61872252
- 批准年份:2018
- 资助金额:64.0 万元
- 项目类别:面上项目
针对内存攻击对象的内存安全防御技术研究
- 批准号:61802432
- 批准年份:2018
- 资助金额:25.0 万元
- 项目类别:青年科学基金项目
相似海外基金
The Proactive and Reactive Neuromechanics of Instability in Aging and Dementia with Lewy Bodies
衰老和路易体痴呆中不稳定的主动和反应神经力学
- 批准号:1074953910749539
- 财政年份:2024
- 资助金额:$ 40.84万$ 40.84万
- 项目类别:
MAIT cells in lupus skin disease and photosensitivity
MAIT 细胞在狼疮皮肤病和光敏性中的作用
- 批准号:1055666410556664
- 财政年份:2023
- 资助金额:$ 40.84万$ 40.84万
- 项目类别:
Effects of Aging on Neuronal Lysosomal Damage Responses Driven by CMT2B-linked Rab7
衰老对 CMT2B 相关 Rab7 驱动的神经元溶酶体损伤反应的影响
- 批准号:1067878910678789
- 财政年份:2023
- 资助金额:$ 40.84万$ 40.84万
- 项目类别:
The role of core circadian regulator Bmal1 in axonal regeneration and nerve repair
核心昼夜节律调节因子 Bmal1 在轴突再生和神经修复中的作用
- 批准号:1067793210677932
- 财政年份:2023
- 资助金额:$ 40.84万$ 40.84万
- 项目类别:
Translational Research and Implementation Science for Nurses (TRAIN) Program 2.0
护士转化研究和实施科学 (TRAIN) 计划 2.0
- 批准号:1068076910680769
- 财政年份:2023
- 资助金额:$ 40.84万$ 40.84万
- 项目类别: