Atypical TDP43 isoforrms driving neurodegeneration in FTD/ALS

非典型 TDP43 亚型导致 FTD/ALS 神经退行性变

基本信息

  • 批准号:
    10534172
  • 负责人:
  • 金额:
    $ 39万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-12-01 至 2024-11-30
  • 项目状态:
    已结题

项目摘要

Cytosolic mislocalization of the RNA binding protein TDP43 and neuronal hyperexcitability are cardinal features of TDP43-related frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Nuclear exclusion and cytosolic deposition of TDP43 are found in over half of those with FTD, and nearly 95% of those with ALS, but the origin of these changes remains unknown. Likewise, neuronal hyperexcitability is a ubiquitous finding in FTD/ALS patients, in vivo and in vitro disease models, yet the cause and consequences of this phenomenon are unclear. Our preliminary data show for the first time an intrinsic connection between TDP43 deposition and neuronal hyperexcitabilty that may play a pivotal part in the neurodegeneration observed in TDP43-related FTD/ALS. Elevated neuronal activity upregulates an uncommon TDP43 isoform that lacks the canonical, low-complexity carboxy-terminus of the protein. Due to its active nuclear export and its ability to bind full-length (fl)TDP43, This shortened (s)TDP43 isoform is actively exported from the nucleus, accumulates in cytosolic aggregates, and sequestrates full-length (fl)TDP43, thereby recapitulating TDP43 pathology in FTD/ALS. Our central goal with this project is to determine the impact of sTDP43 in FTD/ALS pathogenesis, with a long-term objective of defining novel and effective therapeutic strategies targeting TDP43 homeostasis. We will test the hypothesis that sTDP43 drives neurodegeneration in TDP43-related FTD/ALS by three specific aims. First, we will take advantage of an sTDP43-specific antibody that we developed to determine the prevalence and distribution of sTDP43 accumulation in a large cohort of sporadic and familial FTD/ALS cases curated by the University of Michigan Brain Bank. We will also investigate the impact of sTDP43 on RNA homeostasis, and determine the relationship between sTDP43, stress, and stress granules in disease models. Lastly, we will assess the contribution of sTDP43 to neurodegeneration in rodent primary neurons and human induced pluripotent stem cell-derived neurons from patients carrying FTD/ALS-associated C9orf72 hexanucleotide expansion mutations. At the completion of these studies, we will have delineated a unique disease mechanism leading to neurodegeneration in TDP43-related FTD/ALS, and highlighted potential therapeutic approaches focusing on the abnormal activity-dependent production of toxic TDP43 isoforms.
RNA结合蛋白TDP 43的胞浆定位错误和神经元过度兴奋是主要的 TDP 43相关的额颞叶痴呆(FTD)和肌萎缩侧索硬化(ALS)的特征。核 在超过一半的FTD患者中发现TDP 43的排斥和胞浆沉积,在近95%的FTD患者中发现TDP 43的排斥和胞浆沉积。 但这些变化的起源仍然未知。同样,神经元过度兴奋是一种 在FTD/ALS患者、体内和体外疾病模型中普遍存在,但 这种现象尚不清楚。我们的初步数据首次表明, TDP 43沉积和神经元过度兴奋可能在神经退行性变中起关键作用 在TDP 43相关FTD/ALS中观察到。升高的神经元活性上调一种不常见的TDP 43亚型 缺乏典型的低复杂性的羧基末端的蛋白质。由于其积极的核出口及其 结合全长(fl)TDP 43的能力。这种缩短的TDP 43同种型从细胞核主动输出, 在胞质聚集体中积累,并螯合全长(fl)TDP 43,从而重现TDP 43 FTD/ALS中的病理学。我们这个项目的中心目标是确定sTDP 43在FTD/ALS中的影响 发病机制,长期目标是确定靶向TDP 43的新型有效治疗策略 体内平衡我们将通过以下方法检验sTDP 43驱动TDP 43相关FTD/ALS神经变性的假设: 三个具体目标。首先,我们将利用我们开发的sTDP 43特异性抗体, 确定sTDP 43积累在散发性和家族性大队列中的患病率和分布, FTD/ALS病例由密歇根大学脑库策划。我们还将调查 sTDP 43对RNA稳态的影响,并确定sTDP 43,应激和应激颗粒之间的关系。 疾病模型最后,我们将评估sTDP 43对啮齿动物原发性神经变性的贡献。 神经元和人诱导多能干细胞衍生的神经元,来自携带FTD/ALS相关 C9 orf 72六核苷酸扩增突变。当这些研究完成后,我们将划定一个 导致TDP 43相关FTD/ALS神经退行性变的独特疾病机制,并强调了潜在的 治疗方法集中于毒性TDP 43同种型的异常活性依赖性产生。

项目成果

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Sami Barmada其他文献

Sami Barmada的其他文献

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{{ truncateString('Sami Barmada', 18)}}的其他基金

Spatiotemporal analysis of TDP-43 toxicity and endolysosomal turnover mechanisms
TDP-43毒性和内溶酶体周转机制的时空分析
  • 批准号:
    10626673
  • 财政年份:
    2022
  • 资助金额:
    $ 39万
  • 项目类别:
Atypical TDP43 isoforrms driving neurodegeneration in FTD/ALS
非典型 TDP43 亚型导致 FTD/ALS 神经退行性变
  • 批准号:
    10295762
  • 财政年份:
    2019
  • 资助金额:
    $ 39万
  • 项目类别:
Atypical TDP43 isoforrms driving neurodegeneration in FTD/ALS
非典型 TDP43 亚型导致 FTD/ALS 神经退行性变
  • 批准号:
    10057282
  • 财政年份:
    2019
  • 资助金额:
    $ 39万
  • 项目类别:
RNA decay in amyotrophic lateral sclerosis and frontotemporal lobar degeneration
肌萎缩侧索硬化症和额颞叶变性中的 RNA 衰减
  • 批准号:
    10619646
  • 财政年份:
    2016
  • 资助金额:
    $ 39万
  • 项目类别:
RNA decay in amyotrophic lateral sclerosis and frontotemporal lobar degeneration
肌萎缩侧索硬化症和额颞叶变性中的 RNA 衰减
  • 批准号:
    9973175
  • 财政年份:
    2016
  • 资助金额:
    $ 39万
  • 项目类别:
RNA decay in amyotrophic lateral sclerosis and frontotemporal lobar degeneration
肌萎缩侧索硬化症和额颞叶变性中的 RNA 衰减
  • 批准号:
    9324055
  • 财政年份:
    2016
  • 资助金额:
    $ 39万
  • 项目类别:
RNA decay in amyotrophic lateral sclerosis and frontotemporal lobar degeneration
肌萎缩侧索硬化症和额颞叶变性中的 RNA 衰减
  • 批准号:
    10206705
  • 财政年份:
    2016
  • 资助金额:
    $ 39万
  • 项目类别:
RNA decay in amyotrophic lateral sclerosis and frontotemporal lobar degeneration
肌萎缩侧索硬化症和额颞叶变性中的 RNA 衰减
  • 批准号:
    9750843
  • 财政年份:
    2016
  • 资助金额:
    $ 39万
  • 项目类别:
RNA decay in amyotrophic lateral sclerosis and frontotemporal lobar degeneration
肌萎缩侧索硬化症和额颞叶变性中的 RNA 衰减
  • 批准号:
    10435488
  • 财政年份:
    2016
  • 资助金额:
    $ 39万
  • 项目类别:
Elucidating the Mechanisms Underlying Mutant TDP43-induced Neurodegeneration
阐明突变 TDP43 诱导的神经变性的机制
  • 批准号:
    8725311
  • 财政年份:
    2011
  • 资助金额:
    $ 39万
  • 项目类别:

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