ABSTRACT The misfolding and aggregation of microtubule associated protein tau into insoluble neurofibrillary tangles (NFTs) is a defining pathological hallmark of multiple neurodegenerative diseases such as Alzheimer's disease (AD) and frontotemporal dementia (FTD). While such diseases have been and continue to be a major public health priority, no substantial therapeutic intervention has been developed. Recently, our lab has for the first time demonstrated a strong link between the development of pathological tau fibrils and the formation of stress granules (SGs), or protein-RNA granules which a cell forms under stress to temporarily halt translation and safely preserve mRNA transcripts. Using in vitro cell and primary culture systems, we demonstrated that tau regulates the distribution of a key SG nucleating protein TIA1 and also accelerates SG formation. TIA1 overexpression similarly induced tau misfolding and toxicity. Remarkably, when TIA1 is reduced in vivo using the PS19 mouse model of tauopathy, mice are also protected against pathology while simultaneously showing a rescue in multiple behavioral phenotypes; RNA sequencing has also uncovered major transcriptional abnormalities in PS19 mice strikingly rescued by TIA1 knockdown. I have hypothesized that the association of pathological tau with RNA granules causes dysfunction of mRNA metabolism, including splicing and translation. The objective of this proposal is to investigate this hypothesis through two primary aims. In aim 1, we will use immunohistochemical co-staining of pathological forms of tau with key RBPs of interest such as DDX5, HNRNPA0, PABP, and RPL11 in order to observe the development of SG and RBP pathologies as disease progresses. In aim 2 we will investigate the transcriptional and translational deficits caused by tauopathy using both in vitro and in vivo models. Primary methods include translating ribosome affinity purification (TRAP) as well as RNA sequencing of synaptic fractions from PS19 brain tissue.

PROJECT NARRATIVE Neurodegenerative diseases such as Alzheimer's disease represent serious and expensive public health problems with no effective treatments available. RNA binding protein dysregulation has recently emerged as a key feature in a variety of neurodegenerative disorders, and this project aims to investigate potential mRNA dysfunction which results from interactions between pathological tau and RNA binding proteins. This dysregulation represents a novel and significant opportunity for advancement in understanding the molecular mechanisms underlying tauopathy and potential therapeutic advancement.