Extending the limits of cryo-EM to better understand TTR misfolding and aggregation

扩展冷冻电镜的局限性以更好地了解 TTR 错误折叠和聚集

基本信息

  • 批准号:
    10263946
  • 负责人:
  • 金额:
    $ 26.63万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-09-15 至 2022-05-31
  • 项目状态:
    已结题

项目摘要

Appl ID: 9981223 Grant Number : 1R21 AG067594-01 PI Name : Lander, Gabriel Grant Title : Extending the limits of cryo-EM to better understand TTR misfolding and aggregation PROJECT SUMMARY The conversion of natively folded proteins into non-functional aggregates is associated with a wide range of age-related degenerative diseases, including Alzheimer’s Disease (AD). Of great concern is the prediction that these diseases will become more prevalent in prevalence as our nation’s life expectancy increases. The development of therapeutics to prevent or reverse the protein misfolding events implicated in degenerative diseases has thus become the focus of many investigative efforts. The protein transthyretin (TTR), a thyroxine and holoretinol carrier protein exported to cerebrospinal fluid (CSF) and serum, is one such protein that demonstrates increased propensity to adopt a non-native fold and form insoluble aggregates with age. This process can occur in the native, wild type form of the TTR protein, and is responsible for wild type TTR amyloidosis (also known as senile systemic amyloidosis), which causes restrictive cardiomyopathy. Notably, there is evidence that TTR interacts with the Aβ peptide, thereby preventing Aβ fibril formation and aggregation. Studies demonstrating that the CSF of AD patients contain substantially lower concentrations of TTR than in the CSF of age-matched non-AD individuals supports a neuroprotective role of TTR. We posit that age-related TTR misfolding and aggregation abolishes the capacity of TTR to prevent Aβ fibril formation and the subsequent onset of AD. In order to better understand how a natively folded wild type TTR protein becomes predisposed to misfolding events, we seek funding to develop structural approaches to study both the native and aberrant forms of TTR. Detailed structural information regarding the destabilization and non-native oligomerization of this protein will profoundly impact our understanding of TTR misfolding and fibrillogenesis, and could lead to the development of more potent TTR stabilizing drugs that could restore neuroprotective properties of TTR in AD patients. The first aim we will push the limits of size and resolution attainable by cryo-electron microscopy to examine the high-resolution three-dimensional structures of destabilized TTR tetramers and compare them to tetramers that are stabilized by small molecule ligands, revealing how the incorporation of misfolded subunits or the improper incorporation of natively folded subunits impact TTR stability at an atomic level. The second aim will define the architecture of TTR aggregates with atomic precision in order to shed light on the assembly pathways and how different oligomeric states differentially contribute to a variety of distinct pathogeneses. Notably, since perturbations of the native folding pathway of wild type proteins are the likely cytotoxic drivers of AD, the findings of this work will likely have far-reaching impact beyond TTR amyloidoses.
APPL ID:9981223 批准号:1R21 AG067594-01 少年派姓名:兰德,加布里埃尔 授予标题:扩展冷冻-EM的限制以更好地了解TTR错误折叠和聚集 项目总结 天然折叠的蛋白质转化为无功能的聚集体与许多与年龄相关的退行性疾病有关,包括阿尔茨海默病(AD)。非常令人担忧的是,随着我国预期寿命的增加,这些疾病将变得更加普遍。因此,预防或逆转与退行性疾病有关的蛋白质错误折叠事件的治疗方法的发展已成为许多研究工作的重点。甲状腺激素转运蛋白(TTR)是一种输出到脑脊液(CSF)和血清中的甲状腺激素和全视黄醇载体蛋白,是一种随年龄增长倾向于采用非天然折叠并形成不可溶聚集体的蛋白质。这个过程可以发生在天然的野生型TTR蛋白中,并与野生型TTR淀粉样变性(也称为老年性系统性淀粉样变性)有关,后者会导致限制性心肌病。值得注意的是,有证据表明TtR与Aβ肽相互作用,从而防止Aβ纤维的形成和聚集。研究表明AD患者的脑脊液 与年龄匹配的非阿尔茨海默病患者的脑脊液相比,患者脑脊液中的TTR浓度明显更低,这支持了TTR的神经保护作用。我们假设,与年龄相关的TtR错误折叠和聚集取消了Ttr防止Aβ纤维形成和随后发生AD的能力。为了更好地了解自然折叠的野生型TTR蛋白是如何容易发生错误折叠事件的,我们寻求资金来开发结构方法来研究TTR的天然和异常形式。关于该蛋白失稳和非天然寡聚的详细结构信息将深刻影响我们对TTR错误折叠和纤维形成的理解,并可能导致开发更有效的TTR稳定药物,从而恢复AD患者TTR的神经保护特性。第一个目标,我们将突破冷冻电子显微镜可达到的尺寸和分辨率的极限,研究不稳定的TTR四聚体的高分辨率三维结构,并将它们与小分子配体稳定的四聚体进行比较,揭示错误折叠的亚基或天然折叠的亚基的不正确结合如何在原子水平上影响TTR四聚体的稳定性。第二个目标将以原子精度定义TTR聚集体的结构,以阐明组装途径以及不同的寡聚体状态如何对各种不同的发病机制做出不同的贡献。值得注意的是, 由于野生型蛋白的天然折叠途径的扰动可能是AD的细胞毒性驱动因素,这项工作的发现可能会对TTR淀粉样变性产生深远的影响。

项目成果

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Gabriel C Lander其他文献

Gabriel C Lander的其他文献

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{{ truncateString('Gabriel C Lander', 18)}}的其他基金

Developing minimal purification cryo-EM to understand mitochondrial myopathies
开发最小纯化冷冻电镜来了解线粒体肌病
  • 批准号:
    10732697
  • 财政年份:
    2023
  • 资助金额:
    $ 26.63万
  • 项目类别:
High-speed direct detector for cryo electron microscopy
用于冷冻电子显微镜的高速直接检测器
  • 批准号:
    10440962
  • 财政年份:
    2022
  • 资助金额:
    $ 26.63万
  • 项目类别:
Development of a pipeline for parallel elucidation of protein structures
开发并行阐明蛋白质结构的管道
  • 批准号:
    10434001
  • 财政年份:
    2021
  • 资助金额:
    $ 26.63万
  • 项目类别:
Development of a pipeline for parallel elucidation of protein structures
开发并行阐明蛋白质结构的管道
  • 批准号:
    10231713
  • 财政年份:
    2021
  • 资助金额:
    $ 26.63万
  • 项目类别:
Automated, optimized, intelligent data collection for cryo-EM
冷冻电镜的自动化、优化、智能数据采集
  • 批准号:
    10317907
  • 财政年份:
    2021
  • 资助金额:
    $ 26.63万
  • 项目类别:
Automated, optimized, intelligent data collection for cryo-EM
冷冻电镜的自动化、优化、智能数据采集
  • 批准号:
    10649517
  • 财政年份:
    2021
  • 资助金额:
    $ 26.63万
  • 项目类别:
Automated, optimized, intelligent data collection for cryo-EM
冷冻电镜的自动化、优化、智能数据采集
  • 批准号:
    10491792
  • 财政年份:
    2021
  • 资助金额:
    $ 26.63万
  • 项目类别:
Extending the limits of cryo-EM to better understand TTR misfolding and aggregation
扩展冷冻电镜的局限性以更好地了解 TTR 错误折叠和聚集
  • 批准号:
    9981223
  • 财政年份:
    2020
  • 资助金额:
    $ 26.63万
  • 项目类别:
IMPACTING MITOCHONDRIAL FUNCTION THROUGH ALTERED PROTEASE ACTIVITY
通过改变蛋白酶活性影响线粒体功能
  • 批准号:
    10831938
  • 财政年份:
    2016
  • 资助金额:
    $ 26.63万
  • 项目类别:
Impacting mitochondrial function through altered protease activity
通过改变蛋白酶活性影响线粒体功能
  • 批准号:
    10741597
  • 财政年份:
    2016
  • 资助金额:
    $ 26.63万
  • 项目类别:

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