The impact of tau on RNA and translation in progressive supranuclear palsy

About This Grant

PROJECT SUMMARY There is a fundamental gap in understanding how, in neurodegenerative disorders called tauopathies, such as Alzheimer’s Disease and Progressive Supranuclear Palsy (PSP), the protein tau affects memory and neuronal function. One pathological mechanism involves the association of aberrant tau with components of the translation machinery: ribosomes, mRNA, or both. However, the consequences of these interactions remain unknown. The long-term goal of this work is to better understand the link connecting tau abnormalities and memory impairment. The overall objective of this proposal is to determine the impact of pathological tau on translation and, potentially, the impact of translational changes on tau pathogenesis. We will use human brain tissues as well as in vitro and in vivo models to study translation, tau-RNA interactions, and the regulation of protein synthesis in cells and mice neural tissue. Our preliminary results demonstrate an association between tau and ribosome complexes, as well as an impaired protein synthesis network in disease. Therefore, the central hypothesis is that pathological tau impairs translation of proteins critical for memory. The rationale for the proposed research is that understanding the tau-mediated mechanism of translation dysfunction will aid in the design of therapeutic targets for tauopathies, which currently afflict nearly 50 million people worldwide. Our strong preliminary data serve as support for identifying the RNA transcripts that bind to tau in primary tauopathies, such as PSP (Aim 1). Our results also substantiate identifying the compendium of newly translated proteins in the presence of pathological tau (Aim 2). The proposed experiments are highly rigorous by following good practices, statistical design, and controlled validation experiments in each aim. This proposal is significant because it tests a new mechanism in which translation dysfunction promotes symptoms classical of tauopathies, such as memory loss and cognitive impairment. The proposed strategies use novel approaches in human brains and mouse models of tauopathy, which adds substantial innovation. This work is expected to advance the field by filling the gap in understanding of tau-mediated brain dysfunction. This knowledge will serve to better characterize the link between tau and memory impairment in order to develop novel therapeutic strategies.