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
- 来源:
- 关键词:AddressAffectAlzheimer&aposs DiseaseAttentionBehavioralBindingBrain StemCellsCessation of lifeClinicalClustered Regularly Interspaced Short Palindromic RepeatsCytoplasmDataDevelopmentDiseaseEnsureEventFailureFoundationsGene ExpressionGene MutationGenesGeneticHomeostasisImpairmentInformal Social ControlInnovative TherapyLightLinkLiquid substanceMediatingMembraneMessenger RNAModificationMolecularMorphologyMotor NeuronsMusMuscleMuscle FibersMutationNerve DegenerationNervous SystemNeuritesNeurodegenerative DisordersNeuronsOrganellesOutputParalysedPathogenesisPathologyPatternPersonsPhasePhenotypePhysiologicalPost-Transcriptional RegulationPredispositionProcessProteinsPublic HealthRNARNA ProcessingRNA SplicingRNA-Binding ProteinsRegulationResearchRoleSiteSpinalSpinal CordStressTDP-43 aggregationTechniquesTestingTherapeuticTranscriptUp-RegulationVertebral columnWorkage relatedage related neurodegenerationcostdementedembryonic stem cellepitranscriptomeepitranscriptomicsfrontotemporal lobar dementia amyotrophic lateral sclerosishuman diseaseinnovationinsightmotor neuron degenerationmotor neuron functionmouse modelnerve supplynervous system disorderneuron lossneuronal survivalneurotoxicitynovelpharmacologicposttranscriptionalprotein TDP-43protein expressionproteostasissingle nucleus RNA-sequencingspatiotemporalstemtherapeutically effective
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.
概括
痴呆性神经退行性疾病影响数百万人,每年造成的损失超过 3800 亿美元
美元仅在美国。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),
其亚细胞分布和作用的改变被认为导致了许多痴呆症
包括阿尔茨海默病 (AD) 和肌萎缩侧索硬化症 - 额颞叶的临床谱
痴呆症(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
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 的疾病相关突变可以破坏 LLPS 及其随后的作用,但如何
野生型 TDP-43 亚细胞分布和功能在大多数 AD 和 ALS/FTD 病例中发生改变,这
基因突变呈阴性,仍然是个谜。在此,我们建议研究转录后的作用
N6-甲基腺苷 (m6A) 介导的 TDP-43 调节机制。这个想法源于我们的发现
TARDBP(编码 TDP-43 的基因)是胚胎干细胞衍生运动中的 m6A 靶标之一
神经元(ES-MN),其表达受到 m6A 表观转录组调控。我们的中心假设是
TDP-43 上 m6A 标记的丢失会导致其表达及其亚细胞分布和作用发生变化,
这反过来又可能导致神经退行性变。这项研究的基本原理是,一旦知道如何
m6A 介导的 TDP-43 调节有助于神经变性、创新遗传或药理学
可以制定治疗这些人类无法治愈疾病的策略。我们建议首先(AIM 1)
表征 MN 对 m6A 丢失的时空敏感性。据此,我们将定义MN的模式
Mettl3 缺失的小鼠在症状前和症状期均出现脊髓和脑干损失
使用一系列行为、生理和形态学技术的阶段。那么,自从我们初步
数据显示,当 m6A 丢失时,TARDBP 水平会增加,在 AIM 2 中,我们将确定 m6A 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,m6A 耗尽
ES-MN 会导致存活率和神经突生长减少。因此,在 AIM 3 中,我们将提供之间的因果关系
使用基于 CRISPR-Cas 的位点特异性 m6A 导致 TDP-43 的 m6A 依赖性失调和神经变性
TDP-43 mRNA 的编辑。我们的工作有望阐明 m6A 修饰对 TDP-43 亚细胞的作用
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影响
了解 TDP-43 对神经元存活的要求并为表观转录组提供新的靶标
与年龄相关的 TDP-43 蛋白病的调节疗法。
项目成果
期刊论文数量(1)
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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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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