Poly(ADP-ribose) promotes the condensation and toxicity of C9orf72 arginine-rich dipeptide repeat proteins

聚(ADP-核糖)促进 C9orf72 富含精氨酸的二肽重复蛋白的缩合和毒性

基本信息

  • 批准号:
    10298581
  • 负责人:
  • 金额:
    $ 59.81万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-07-15 至 2026-06-30
  • 项目状态:
    未结题

项目摘要

A GGGGCC hexanucleotide repeat expansion in the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two devastating neurodegenerative diseases with no effective treatment. We have shown that transcripts of the expanded repeat undergo an unconventional mode of translation, resulting in the production of five dipeptide repeat proteins (DPRs). Our group and others demonstrated that DPRs form neuronal inclusions throughout the central nervous system of patients with C9orf72-associated ALS and FTD (“c9ALS/FTD”). The identification of this neuropathological hallmark shed new light on possible disease mechanisms, and our systematic assessment of DPRs in human tissues, along with their evaluation in mice and other preclinical models, indicate that the arginine-rich DPRs, poly(GR) and poly(PR), are especially toxic. Our data further suggest that this toxicity stems, at least in part, from the co-condensation and/or co-aggregation of these DPR proteins with proteins that regulate essential cellular functions, such as stress granule biology and nucleocytoplasmic transport. We have also shown that poly(GR) aggregation induces TDP-43 pathology, another hallmark feature of c9ALS/FTD and of the majority of sporadic ALS and FTD cases. Nevertheless, since poly(GR) and poly(PR) interact with more than 200 endogenous proteins, they are likely to adversely influence a host of cellular functions – a line of investigation that merits attention. Also of importance is determining the underlying factors that regulate poly(GR) and poly(PR) condensation and aggregation, and their interactions with other proteins. It is thus notable that our preliminary data show that poly(ADP-ribose) (PAR) promotes poly(GR) and poly(PR) condensation, and enhances their co-condensation or co-aggregation with disease-related proteins in vitro. Moreover, we observed that reducing PAR suppresses poly(GR)- or poly(PR)-mediated neurodegeneration in Drosophila. In light of these exciting findings, we hypothesize that PAR mediates the aggregation and toxicity of arginine-rich DPRs and the proteins to which they bind. Thus, the goal of the proposed project is to determine how PAR does so. To this end, we will identify proteins that interact with poly(GR) or poly(PR) in a PAR-dependent fashion, and investigate the contribution of PAR to arginine-rich DPR aggregation and toxicity using multiple preclinical models and brain tissues from C9orf72 expansion carriers. Overall, by availing the diverse expertise of our team members, we endeavor to elucidate the role of PAR and arginine-rich DPR proteins in c9ALS/FTD pathogenesis, and thus uncover novel therapeutic targets to expedite the development of effective treatments for c9ALS/FTD.
C9 orf 72基因中的GGGGCC六核苷酸重复扩增是最常见的遗传原因。 肌萎缩侧索硬化症(ALS)和额颞叶痴呆症(FTD),两种毁灭性的神经退行性疾病, 没有有效治疗的疾病。我们已经证明,扩增重复序列的转录本经历了一个 非传统的翻译模式,导致产生五个二肽重复蛋白(DPR)。我们 研究小组和其他人证明,DPRs在整个中枢神经系统中形成神经元包涵体, C9 orf 72相关ALS和FTD患者(“c9 ALS/FTD”)。这种神经病理学的鉴定 hallmark为可能的疾病机制提供了新的线索,我们对人类DPR的系统评估 组织,沿着它们在小鼠和其它临床前模型中的评价,表明富含精氨酸的DPR, 聚(GR)和聚(PR)尤其有毒。我们的数据进一步表明,这种毒性至少部分源于, 从这些DPR蛋白与调节必需蛋白质的共缩合和/或共聚集, 细胞功能,如应激颗粒生物学和核质运输。我们还表明, 聚(GR)聚集诱导TDP-43病理学,这是c9 ALS/FTD的另一个标志性特征, 散发的ALS和FTD病例。然而,由于聚(GR)和聚(PR)与200多个 内源性蛋白质,它们可能会对许多细胞功能产生不利影响-一系列研究 值得注意的同样重要的是确定调节多聚(GR)的潜在因素, 聚(PR)缩合和聚集,以及它们与其他蛋白质的相互作用。值得注意的是,我们的 初步数据显示,聚(ADP-核糖)(PAR)促进聚(GR)和聚(PR)缩合, 在体外增强它们与疾病相关蛋白的共缩合或共聚集。而且我们 观察到减少PAR抑制果蝇中多聚GR或多聚PR介导的神经变性。在 鉴于这些令人兴奋的发现,我们假设PAR介导了富含精氨酸的聚体的聚集和毒性。 DPR和它们所结合的蛋白质。因此,拟议项目的目标是确定PAR如何 这样做。为此,我们将鉴定在PAR依赖性蛋白质中与poly(GR)或poly(PR)相互作用的蛋白质。 的方式,并研究PAR的贡献,富含精氨酸DPR聚集和毒性使用多个 临床前模型和来自C9 orf 72扩增载体的脑组织。总的来说,通过利用不同的专业知识, 我们的团队成员,我们奋进阐明PAR和富含精氨酸的DPR蛋白在c9 ALS/FTD中的作用, 发病机制,从而发现新的治疗靶点,以加快有效治疗的发展 c9ALS/FTD。

项目成果

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Tania France Gendron其他文献

Tania France Gendron的其他文献

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{{ truncateString('Tania France Gendron', 18)}}的其他基金

Poly(ADP-ribose) promotes the condensation and toxicity of C9orf72 arginine-rich dipeptide repeat proteins
聚(ADP-核糖)促进 C9orf72 富含精氨酸的二肽重复蛋白的缩合和毒性
  • 批准号:
    10707931
  • 财政年份:
    2021
  • 资助金额:
    $ 59.81万
  • 项目类别:
Poly(ADP-ribose) promotes the condensation and toxicity of C9orf72 arginine-rich dipeptide repeat proteins
聚(ADP-核糖)促进 C9orf72 富含精氨酸的二肽重复蛋白的缩合和毒性
  • 批准号:
    10448297
  • 财政年份:
    2021
  • 资助金额:
    $ 59.81万
  • 项目类别:
Frontotemporal dementia and related disorders: transcriptomic profiling, biomarker discovery, and mechanistic insight
额颞叶痴呆及相关疾病:转录组分析、生物标志物发现和机制洞察
  • 批准号:
    10180652
  • 财政年份:
    2021
  • 资助金额:
    $ 59.81万
  • 项目类别:
Frontotemporal dementia and related disorders: transcriptomic profiling, biomarker discovery, and mechanistic insight
额颞叶痴呆及相关疾病:转录组分析、生物标志物发现和机制洞察
  • 批准号:
    10392505
  • 财政年份:
    2021
  • 资助金额:
    $ 59.81万
  • 项目类别:
Frontotemporal dementia and related disorders: transcriptomic profiling, biomarker discovery, and mechanistic insight
额颞叶痴呆及相关疾病:转录组分析、生物标志物发现和机制洞察
  • 批准号:
    10597677
  • 财政年份:
    2021
  • 资助金额:
    $ 59.81万
  • 项目类别:
Core C
核心C
  • 批准号:
    10582720
  • 财政年份:
    2014
  • 资助金额:
    $ 59.81万
  • 项目类别:
Core C
核心C
  • 批准号:
    10415045
  • 财政年份:
    2014
  • 资助金额:
    $ 59.81万
  • 项目类别:
Pathologically modified TDP-43 in neurodegenerative diseases
病理修饰的 TDP-43 在神经退行性疾病中的应用
  • 批准号:
    8263381
  • 财政年份:
    2011
  • 资助金额:
    $ 59.81万
  • 项目类别:
Pathologically modified TDP-43 in neurodegenerative diseases
病理修饰的 TDP-43 在神经退行性疾病中的应用
  • 批准号:
    8093934
  • 财政年份:
    2011
  • 资助金额:
    $ 59.81万
  • 项目类别:

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