Neuronal Tau-RNA interactions in health and disease

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.

Neuronal dysfunction in Alzheimer's (AD) and related neurodegenerative diseases correlates with abnormal cellular distribution, post-translational modifications, and intraneuronal aggregation of Tau protein. Intrinsic protein disorder allows physiological Tau to engage in conditional Tau protein-protein and protein-organelle interactions, including interactions with RNA-containing protein assemblies like ribosomes, RNA-protein granules, and nuclear speckles. Moreover, Tau has a high affinity to RNA, and Tau-RNA interaction can influence Tau microtubule binding and promote Tau aggregation. The (patho)physiological role of Tau:RNA interactions remains understudied though. Own preliminary iCLIP data and published data from cells show that Tau interacts with ribosomal and other non-coding RNAs (ncRNAs). Here, we propose to use iCLIP to decipher human neuronal Tau:RNA interactions in physiological versus pro-pathological stress conditions, study Tau:ncRNA molecular interactions and determine the effect on ribosome function and chromatin, develop strategies to molecularly block selected Tau:ncRNA interactions, and explore the relevance of these findings in human neurons. The Tau:ncRNA interactomes and molecular mechanistic insides generated in this work will elucidate the role of ncRNAs in Tau (patho)biology and therefore have an impact far beyond this proposal.