Protection from pathological tau by activation of the ER unfolded protein response

通过激活 ER 未折叠蛋白反应来预防病理性 tau 蛋白

基本信息

项目摘要

Pathological deposition of abnormal aggregated tau protein in neurons is one of the diagnostic hallmarks of Alzheimer's disease (AD) and related dementia (ADRD). How pathological tau causes dysfunction and degeneration of neurons remains an enigma. However, neuronal dysfunction and neurodegeneration clearly cause dementia. To understand how abnormal tau contributes to neurodegeneration in AD and ADRD, we established a transgenic model in C. elegans for neurodegeneration driven by human tau aggregation. In our previous work, we identified XBP-1, the master transcriptional regulator of the unfolded protein response (UPR), as a critical regulator of pathological tau accumulation and toxicity. ER stress and activation of the UPR have clearly been implicated in human tauopathy disorders by other laboratories although the functional consequences of UPR activation on tau pathology remain unclear. We have leveraged our C. elegans model of tauopathy to dissect the functional role of the UPR in tau pathology. We have found that tau pathology can induce ER stress, and that UPR activation protects against tauopathy through XBP-1s. We hypothesize that XBP-1s target genes can modulate accumulation and clearance of pathological tau. To test this hypothesis, we upregulated the UPR in neurons in the absence of ER stress, using a constitutively active XBP-1s expressing transgene. Transcriptomic studies of this system have revealed key XBP-1s target genes that modulate tauopathy and cross talk with other regulatory branches of the UPR (ATF6 and PERK branches). Given the high level of conservation of the UPR system between mammals and C. elegans, we propose to utilize the existing model and transgenes to dissect the mechanism by which the UPR protects against tau neurotoxicity. The Specific Aims of this project are to: 1) Identify the molecular mechanisms of XBP1s mediated suppression of tauopathy; 2) Examine UPR branch crosstalk contributing to tau clearance and ER associated degradation, 3) Address the disease relevance of XBP-1s target genes to neurodegeneration in both human disease and mouse models of tauopathy. Completion of the project as proposed will inform the molecular mechanisms by which the UPR participates in tauopathy. We will also explore the neuroprotective translational potential of XBP-1s mediated tau clearance in the mammalian brain.
神经元中异常聚集的tau蛋白的病理性沉积是诊断的方法之一 阿尔茨海默病(AD)和相关痴呆(ADRD)的标志。病理性tau蛋白如何导致 神经元的功能障碍和退化仍然是一个谜。然而,神经元功能障碍和 神经退化显然会导致痴呆为了了解异常的tau蛋白如何影响 在AD和ADRD的神经退行性变中,我们建立了C.优雅的, 由人类tau聚集驱动的神经变性。在我们以前的工作中,我们确定了XBP-1, 未折叠蛋白反应(UPR)的主要转录调节因子,作为 病理性tau积聚和毒性。ER应激和UPR的激活已经清楚地 在人类tau蛋白病疾病的其他实验室,虽然功能性后果 UPR激活对tau病理学的影响尚不清楚。我们利用了我们的C。elegans模型 tau蛋白病的研究,以剖析UPR在tau蛋白病中的功能作用。我们发现tau蛋白病理学 可诱导ER应激,UPR激活可通过XBP-1保护tau蛋白病。我们 假设XBP-1 s靶向基因可以调节病理性tau积累和清除。 为了验证这一假设,我们在没有ER应激的情况下上调了神经元中的UPR,使用了一种新的方法。 表达转基因的组成型活性XBP-1。该系统的转录组学研究 揭示了XBP-1 s调节tau蛋白病的关键靶基因,并与其他调节因子发生交叉作用。 普遍定期审议的分支(ATF 6和PERK分支)。鉴于普遍定期审议的高度保守性, 哺乳动物与C.我们建议利用现有的模型和转基因, 剖析UPR保护tau神经毒性的机制。的具体目标 本研究的主要目的是:1)确定XBP 1 s介导的抑制细胞凋亡的分子机制。 tau蛋白病; 2)检查有助于tau蛋白清除和ER相关的UPR分支串扰 3)解决XBP-1 s靶基因与神经变性的疾病相关性, 人类疾病和tau蛋白病的小鼠模型。如按建议完成项目, 告知UPR参与tau蛋白病的分子机制。我们还将探索 XBP-1 s介导的哺乳动物脑中tau蛋白清除的神经保护翻译潜力。

项目成果

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Brian C. Kraemer其他文献

Erratum to: Ethosuximide ameliorates neurodegenerative disease phenotypes by modulating DAF-16/FOXO target gene expression
  • DOI:
    10.1186/s13024-015-0051-6
  • 发表时间:
    2015-10-23
  • 期刊:
  • 影响因子:
    17.500
  • 作者:
    Xi Chen;Hannah V. McCue;Shi Quan Wong;Sudhanva S. Kashyap;Brian C. Kraemer;Jeff W. Barclay;Robert D. Burgoyne;Alan Morgan
  • 通讯作者:
    Alan Morgan
TMEM106B C-terminal fragments aggregate and drive neurodegenerative proteinopathy
TMEM106B C 端片段聚集并驱动神经退行性蛋白病
  • DOI:
    10.1101/2024.06.11.598478
  • 发表时间:
    2024
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Ruben Riordan;Aleen D. Saxton;P. McMillan;Rebecca L. Kow;Nicole F. Liachko;Brian C. Kraemer
  • 通讯作者:
    Brian C. Kraemer
Yeast three-hybrid system to detect and analyze RNA-protein interactions.
用于检测和分析 RNA-蛋白质相互作用的酵母三杂交系统。
  • DOI:
  • 发表时间:
    2000
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Beilin Zhang;Brian C. Kraemer;D. Sengupta;S. Fields;Marvin Wickens
  • 通讯作者:
    Marvin Wickens
α-Methyl-α-phenylsuccinimide ameliorates neurodegeneration in a <em>C. elegans</em> model of TDP-43 proteinopathy
  • DOI:
    10.1016/j.nbd.2018.06.013
  • 发表时间:
    2018-10-01
  • 期刊:
  • 影响因子:
  • 作者:
    Shi Quan Wong;Matthew G. Pontifex;Marie M. Phelan;Chandra Pidathala;Brian C. Kraemer;Jeff W. Barclay;Neil G. Berry;Paul M. O'Neill;Robert D. Burgoyne;Alan Morgan
  • 通讯作者:
    Alan Morgan
Alternative 3′ UTR polyadenylation is disrupted in the rNLS8 mouse model of ALS/FTLD
  • DOI:
    10.1186/s13041-025-01174-1
  • 发表时间:
    2025-01-14
  • 期刊:
  • 影响因子:
    2.900
  • 作者:
    Randall J. Eck;Paul N. Valdmanis;Nicole F. Liachko;Brian C. Kraemer
  • 通讯作者:
    Brian C. Kraemer

Brian C. Kraemer的其他文献

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{{ truncateString('Brian C. Kraemer', 18)}}的其他基金

SPOP drives neurodegenerative tauopathy
SPOP 驱动神经退行性 tau 病
  • 批准号:
    10734807
  • 财政年份:
    2023
  • 资助金额:
    $ 52万
  • 项目类别:
Targeting MSUT2 with small molecules to ameliorate pathological tau
用小分子靶向 MSUT2 改善病理性 tau
  • 批准号:
    10735826
  • 财政年份:
    2023
  • 资助金额:
    $ 52万
  • 项目类别:
Formation of Tau RNA Complexes disrupts tau function and drives tau neuropathology
Tau RNA 复合物的形成会破坏 tau 功能并驱动 tau 神经病理学
  • 批准号:
    10777174
  • 财政年份:
    2023
  • 资助金额:
    $ 52万
  • 项目类别:
Developing MSUT2 Nanobodies for Targeting Pathological Tau in Alzheimer's Disease
开发 MSUT2 纳米抗体来靶向阿尔茨海默病中的病理性 Tau 蛋白
  • 批准号:
    10518408
  • 财政年份:
    2022
  • 资助金额:
    $ 52万
  • 项目类别:
Developing MSUT2 Nanobodies for Targeting Pathological Tau in Alzheimer's Disease
开发 MSUT2 纳米抗体来靶向阿尔茨海默病中的病理性 Tau 蛋白
  • 批准号:
    10363866
  • 财政年份:
    2022
  • 资助金额:
    $ 52万
  • 项目类别:
Reversal of Tau Pathology with MSUT2 siRNA Conjugates
使用 MSUT2 siRNA 缀合物逆转 Tau 病理学
  • 批准号:
    10240452
  • 财政年份:
    2020
  • 资助金额:
    $ 52万
  • 项目类别:
Reversal of Tau Pathology with MSUT2 siRNA Conjugates
使用 MSUT2 siRNA 缀合物逆转 Tau 病理学
  • 批准号:
    9909831
  • 财政年份:
    2020
  • 资助金额:
    $ 52万
  • 项目类别:
Protection from pathological tau by activation of the ER unfolded protein response
通过激活 ER 未折叠蛋白反应来预防病理性 tau 蛋白
  • 批准号:
    10551219
  • 财政年份:
    2020
  • 资助金额:
    $ 52万
  • 项目类别:
Protection from pathological tau by activation of the ER unfolded protein response
通过激活 ER 未折叠蛋白反应来预防病理性 tau 蛋白
  • 批准号:
    9901055
  • 财政年份:
    2020
  • 资助金额:
    $ 52万
  • 项目类别:
Inhibiting pathological TDP-43 phosphorylation as a therapeutic strategy for ALS
抑制病理性 TDP-43 磷酸化作为 ALS 的治疗策略
  • 批准号:
    9348132
  • 财政年份:
    2017
  • 资助金额:
    $ 52万
  • 项目类别:

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