METTL3-mediated regulation of motor neuron function

METTL3介导的运动神经元功能调节

基本信息

  • 批准号:
    10781077
  • 负责人:
  • 金额:
    $ 41.13万
  • 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:
    2023-09-30 至 2028-07-31
  • 项目状态:
    未结题

项目摘要

SUMMARY Dementing neurodegenerative diseases affect millions of people and have an annual cost exceeding $380 billion dollars in the USA alone. To gain insights into potential effective therapeutic strategies for these incurable disorders, herein we focused our attention on the RNA-binding protein TAR DNA-binding protein-43 (TDP-43), whose altered subcellular distribution and role are thought to contribute to a number of dementing disorders including Alzheimer’s disease (AD) and the clinical spectrum of amyotrophic lateral sclerosis-frontotemporal dementia (ALS/FTD). TDP-43, like other RNA-binding proteins with low-complexity domains are involved in the formation of membrane-less organelles associated with RNA processing via liquid-liquid phase separation (LLPS) assembly. While disease-associated mutations in TDP-43 can disrupt LLPS and its ensuing roles, how wild-type TDP-43 subcellular distribution and function are altered in the majorly of AD and ALS/FTD cases, which are gene mutation negative, remain enigmatic. We propose, herein, to investigate the role of post-transcriptional regulatory mechanisms of TDP-43 mediated by N6-methyladenosine (m6A). This idea stems from our finding that TARDBP, the gene encoding for TDP-43, is among the m6A targets in embryonic stem cell-derived motor neurons (ES-MNs) and that its expression is under m6A epitranscriptomic regulation. Our central hypothesis is that loss of m6A marks on TDP-43 causes changes in its expression and in its subcellular distribution and role, which, in turn, may contribute to neurodegeneration. The rationale for this research is that, once it is known how m6A-mediated regulation of TDP-43 contributes to neurodegeneration, innovative genetic or pharmacological strategies can be devised for the treatment of these incurable human diseases. We propose to first (AIM 1) characterize the spatiotemporal susceptibility of MNs to m6A loss. Accordingly, we will define the pattern of MN loss in both spinal cord and brainstem in mice with Mettl3 depletion at both presymptomatic and symptomatic stages using a battery of behavioral, physiological and morphological techniques. Then, since our preliminary data show that TARDBP levels are increased when m6A is lost, in AIM 2, we will determine how the loss of m6A impairs TDP-43 expression and its subcellular localization. Our preliminary data also show that m6A depletion in ES-MNs results in reduced survival and neurite outgrowth. Thus, in AIM 3, we will provide a causal link between m6A-dependent dysregulation of TDP-43 and neurodegeneration by using CRISPR-Cas-based site-specific m6A editing of TDP-43 mRNA. Our work is expected to elucidate the role of m6A modification on TDP-43 subcellular distribution and functions. Thus, our findings will have a positive impact by advancing our mechanistic understanding of TDP-43 requirement for neuronal survival and by providing new targets for epitranscriptome- modulating therapies for age-related TDP-43 proteinopathies.
总结 痴呆性神经退行性疾病影响数百万人,每年的费用超过3800亿美元 仅在美国就有美元。深入了解这些不治之症的潜在有效治疗策略 疾病,在此我们将注意力集中在RNA结合蛋白TAR DNA结合蛋白-43(TDP-43), 其改变的亚细胞分布和作用被认为是导致许多痴呆症的原因 包括阿尔茨海默病(AD)和额颞肌萎缩侧索硬化症的临床谱 痴呆(ALS/FTD)。TDP-43与其他具有低复杂性结构域的RNA结合蛋白一样,参与了 通过液-液相分离形成与RNA加工相关的无膜细胞器 (LLPS)组装。虽然TDP-43中的疾病相关突变可以破坏LLPS及其随后的作用, 野生型TDP-43亚细胞分布和功能在AD和ALS/FTD病例中主要发生改变, 基因突变阴性,仍然是个谜我们建议,在此,调查的作用,转录后 N6-甲基腺苷(m6 A)介导的TDP-43的调节机制。这个想法源于我们的发现 TDP-43的编码基因TARDBP是胚胎干细胞来源的运动神经元中的m6 A靶点之一。 神经元(ES-MN),其表达受m6 A表转录调控。我们的核心假设是 TDP-43上m6 A标记的缺失导致其表达及其亚细胞分布和作用的变化, 这反过来可能导致神经退化这项研究的基本原理是,一旦知道如何 m6 A介导的TDP-43调节有助于神经变性,创新的遗传或药理学 可以设计出治疗这些人类不治之症的策略。我们建议首先(AIM 1) 表征MN对m6 A损失的时空易感性。因此,我们将定义MN的模式 在症状前和有症状时Mettl 3耗尽的小鼠中脊髓和脑干的损失 阶段使用电池的行为,生理和形态技术。既然我们的初步调查 数据显示,当m6 A丢失时,TARDBP水平会增加,在AIM 2中,我们将确定m6 A的丢失如何 损害TDP-43表达及其亚细胞定位。我们的初步数据还表明, ES-MN导致存活和神经突生长减少。因此,在AIM 3中,我们将提供 通过使用基于CRISPR-Cas的位点特异性m6 A,TDP-43和神经变性的m6 A依赖性失调 TDP-43 mRNA的编辑。我们的工作有望阐明m6 A修饰对TDP-43亚细胞凋亡的作用。 分布和功能。因此,我们的发现将通过推进我们的机制产生积极的影响。 了解TDP-43对神经元存活的需求,并为表转录组提供新的靶点, 用于年龄相关的TDP-43蛋白质病的调节疗法。

项目成果

期刊论文数量(1)
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会议论文数量(0)
专利数量(0)

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Francesco Lotti其他文献

Francesco Lotti的其他文献

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{{ truncateString('Francesco Lotti', 18)}}的其他基金

Developing RNA therapeutics for rare neurodevelopmental disorders
开发罕见神经发育障碍的 RNA 疗法
  • 批准号:
    10697291
  • 财政年份:
    2023
  • 资助金额:
    $ 41.13万
  • 项目类别:
SMN post-translational modification in Spinal Muscular Atrophy
SMN 翻译后修饰在脊髓性肌萎缩症中的应用
  • 批准号:
    9387954
  • 财政年份:
    2017
  • 资助金额:
    $ 41.13万
  • 项目类别:

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