Neuronal Tau-RNA interactions in health and disease

健康和疾病中神经元 Tau-RNA 相互作用

• 批准号: MR/Y012151/1
• 负责人: Jernej Ule
• 金额: $ 24.01万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FY012151%2F1
• 关键词: Neuronal; Tau; RNA; interactions; health

Neuronal dysfunction in Alzheimer's (AD) and related neurodegenerative diseases correlates with the aggregation of the microtubule associated protein Tau. Tau seems to induce a number of cellular changes that are mediated by disease-conditional interactions of Tau with other proteins, organelles, and RNA molecules. Moreover, Tau has a high affinity to RNA, and Tau:RNA interactions were shown to influence its canonical function in microtubule binding and promote its aggregation. The (patho)physiological role of Tau:RNA interactions remains understudied though. Our own preliminary data and published work show that Tau interacts with ribosomal and other non-coding RNAs (ncRNAs). Here, we aim to decipher the interactions of Tau with ncRNAs and determine their impact on ribosome function and chromatin regulation, processes that are altered in response to Tau. We will decipher neuronal Tau:RNA interactions in physiological versus pro-pathological stress conditions, study Tau:ncRNA interactions on the molecular level and determine the impact on key cellular processes, develop strategies to block abnormal Tau:ncRNA interactions, and explore the relevance of these findings for Tau biology in human neurons. The findings of this work will for the first time elucidate the role of ncRNAs in Tau (patho)biology and therefore have a large impact far beyond this proposal.

阿尔茨海默病（AD）和相关神经退行性疾病中的神经元功能障碍与微管相关蛋白Tau的聚集相关。Tau似乎诱导许多细胞变化，这些变化是由Tau与其他蛋白质、细胞器和RNA分子的疾病条件性相互作用介导的。此外，Tau对RNA具有高亲和力，并且Tau：RNA相互作用显示出影响其在微管结合中的典型功能并促进其聚集。然而，Tau：RNA相互作用的（病理）生理作用仍然研究不足。我们自己的初步数据和已发表的工作表明，Tau与核糖体和其他非编码RNA（ncRNA）相互作用。在这里，我们的目标是破译Tau与ncRNA的相互作用，并确定它们对核糖体功能和染色质调节的影响，这些过程在响应Tau时发生了改变。我们将破译神经元Tau：RNA在生理与亲病理应激条件下的相互作用，研究Tau：ncRNA在分子水平上的相互作用，并确定对关键细胞过程的影响，制定策略来阻断异常Tau：ncRNA相互作用，并探索这些发现与人类神经元中Tau生物学的相关性。这项工作的发现将首次阐明ncRNA在Tau（病理）生物学中的作用，因此具有远远超出这一提议的巨大影响。