Tau protein proteolysis signaling in Alzheimer's disease

阿尔茨海默病中的 Tau 蛋白水解信号

基本信息

  • 批准号:
    10728202
  • 负责人:
  • 金额:
    $ 43.18万
  • 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:
    2023-08-15 至 2025-07-31
  • 项目状态:
    未结题

项目摘要

Project Summary Pathologic Tau protein self-assembly templating and stereotypical regional spreading along neuronal networks correlates with loss of neurons and is central to clinical progression and staging in Alzheimer’s disease (AD). In diseased brain, Tau molecules begin to form filamentous aggregates with a rigid β-sheet rich core. Although some Tau protein fragments can spontaneously aggregate, recombinant full-length Tau produced in vitro or when expressed in mammalian cells does not aggregate spontaneously even at supersaturation. To initiate Tau protein to form aggregates, some unknown energy barrier must be overcome. Research shows that inducing Tau monomer to form a nucleus leading to filamentous elongation can be a heterogenous association such as with a membrane, small molecules, or peptides stabilizing the misfolded species for subsequent elongation steps. Proteolysis is a process of protein degradation which also controls multiple cellular functions. Tau is a natively unfolded protein sensitive to protease digestion and the longest human brain isoform contains more than forty cleavage sites which leads to hundreds of possible Tau-derived peptides. Peptides have been shown to rapidly induce the misfolding and aggregation of tau in vitro and in mammalian cells. Here we propose to test and rank the propensity of Tau aggregation induction by each protease-cleaved Tau peptide after incubation with full-length recombinant Tau isoforms and subsequently capture aggregate gross morphology using transmission electron microscopy (TEM). Intracellular signaling activity by Tau peptides will be detected in cell culture to further characterize each peptide. Peptides inducing full-length Tau protein to aggregate or having active cellular signaling properties may implicate protease components dysregulated in disease. Because many known cleavage sites on Tau protein remain uncharacterized, this study aims to collect preliminary data for future funding and will begin groundwork for long-term research of proteolytic post- translational modification to identify those sites on Tau which may produce toxic peptides in neurons.
项目摘要 病理性Tau蛋白自组装模板和沿沿着神经元网络的定型区域扩散 与神经元的损失相关,并且是阿尔茨海默病(AD)的临床进展和分期的中心。在 在患病的脑中,Tau分子开始形成具有刚性β-折叠富集核心的丝状聚集体。虽然 一些Tau蛋白片段可以自发聚集,体外产生的重组全长Tau或 当在哺乳动物细胞中表达时,即使在过饱和下也不会自发聚集。发起 Tau蛋白要形成聚集体,必须克服一些未知的能量障碍。研究表明 诱导Tau单体形成导致丝状伸长的核可以是异源缔合 例如用膜、小分子或肽稳定错误折叠的种类, 延伸步骤。蛋白质水解是蛋白质降解的过程,也控制着多种细胞功能。 Tau是对蛋白酶消化敏感的天然未折叠蛋白质,并且最长的人脑同种型含有 超过40个切割位点,导致数百种可能的Tau衍生肽。肽已经 显示在体外和哺乳动物细胞中快速诱导tau的错误折叠和聚集。这里我们 建议测试和排序由每种蛋白酶切割的Tau肽诱导Tau聚集的倾向 在与全长重组Tau同种型孵育并随后捕获聚集体后, 使用透射电子显微镜(TEM)观察形态。Tau肽的细胞内信号传导活性将 在细胞培养物中检测,以进一步表征每种肽。诱导全长Tau蛋白的肽 聚集或具有活性细胞信号传导特性可能涉及蛋白酶组分在细胞内失调, 疾病由于Tau蛋白上的许多已知切割位点仍然没有被表征,因此本研究旨在 为未来的资金收集初步数据,并将开始为蛋白水解后的长期研究奠定基础, 翻译修饰以鉴定Tau上可能在神经元中产生毒性肽的那些位点。

项目成果

期刊论文数量(0)
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科研奖励数量(0)
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专利数量(0)

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Carol J. Huseby其他文献

Cellular models for the investigation of the structural dynamics and activity of human tau protein aggregate formation
  • DOI:
    10.1016/j.bpj.2022.11.436
  • 发表时间:
    2023-02-10
  • 期刊:
  • 影响因子:
  • 作者:
    Eranjalee Ranaweera;Carol J. Huseby;Debra T. Hansen;Po-Lin Chiu;Paul Coleman;Petra Fromme
  • 通讯作者:
    Petra Fromme

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