Neuronal Tau-RNA interactions in health and disease

阿尔茨海默病(AD)和相关神经退行性疾病的神经元功能障碍与微管相关蛋白Tau的聚集有关。Tau似乎诱导了许多细胞变化，这些变化是由Tau与其他蛋白质、细胞器和RNA分子的疾病条件相互作用所介导的。此外，Tau对RNA有很高的亲和力，Tau与RNA的相互作用影响了它在微管结合中的典型功能，并促进了它的聚集。然而，Tau：RNA相互作用的(病理)生理作用仍未得到充分研究。我们自己的初步数据和发表的工作表明，Tau与核糖体和其他非编码RNA(NcRNAs)相互作用。在这里，我们的目标是破译Tau与ncRNAs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，这些过程是随着Tau的反应而改变的。我们将破译生理和病理应激条件下神经元Tau：RNA的相互作用，在分子水平上研究Tau：ncRNA的相互作用并确定其对关键细胞过程的影响，开发阻断异常的Tau：ncRNA相互作用的策略，并探索这些发现与人类神经元Tau生物学的相关性。这项工作的发现将首次阐明ncRNAs在Tau(Patho)生物学中的作用，因此产生的影响远远超过这一提议。

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.