RNA-Related Function and Dysfunction of Tau in FTD

Aggregation of the protein tau is a hallmark of several neurodegenerative diseases, collectively called tauopathies, which include Alzheimer’s disease (AD) and frontotemporal dementia (FTD). The presence of tau aggregates is highly correlated with disease progression, and there are disease-causing mutations in the tau- encoding gene, MAPT, but the molecular mechanisms linking pathological tau to neuronal dysfunction are not well understood. Dysregulation of RNA processing and metabolism are well-established properties of some neurodegenerative diseases. Tau is a known RNA binding protein (RBP), but there is little known about RNA dysregulation in tauopathies, and there is no known function of tau-RNA interactions in neurons, the discovery of which could lead to breakthroughs in deciphering the molecular determinants of tauopathies. In a collaboration with another trainee in the Kampmann Lab, I have demonstrated that iPSC-derived neurons harboring the FTD-causing MAPT V337M mutation display an aberrant axonogenesis signature linked to decreased phosphorylation of tau and other microtubule-associated proteins. In unpublished work, I have uncovered dysregulated RNA processing and localization as another consequence of MAPT knockdown (KD) and to a greater extent V337M mutation, which may contribute to axon phenotypes as well as FTD-relevant changes to cellular function, including V337M-induced hyperexcitability. It is my hypothesis that tau associates with RBPs to facilitate mRNA stability and transport along microtubules and that disruptions in mRNA processing and localization in V337M neurons are a direct result of aberrant tau functionality in this context. The goal of this proposal is to (1) characterize tau function in the context of RNA processing and transport and (2) identity mechanisms of tau-induced RNA dysregulation in FTD. I have shown that tau KD neurons and to a greater extent MAPT V337M neurons display altered RBP levels and phosphorylation as well as abnormal mRNA localization and exon usage. In Aim 1, I will acquire training in molecular RNA biology and in vitro biochemistry to characterize tau-RNA interactions in mRNA transport. In Aim 2, I will obtain training in spatial transcriptomics and RNA visualization to identify mislocalized and/or misprocessed mRNAs in FTD brain tissue. I will also expand my expertise in CRISPRi screening to discover modifiers of V337M tau- induced mRNA misprocessing. I am ideally positioned to complete the proposed research as this proposal complements my training in epigenetics and functional genomics in iPSC-derived neurons with RNA-based techniques and patient brain sample research. Completion of this proposal will transition promising molecular data to an interdisciplinary characterization of a novel and sometimes toxic tau function, supported by patient- derived data and directly relevant to therapeutic testing. The enclosed training plan will provide me the necessary scientific expertise and executive training to launch my career as an independent scientist.