Contributions of tau-mediated translational dysregulation to pathogenesis and progression of fronto-temporal dementia

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Abstract There is a fundamental gap in understanding how mutations on P301 of tau cause memory impairment in fronto-temporal dementia (FTD). One pathological mechanism involves the association of aberrant tau with ribosomal complexes. However, the consequences of this interaction are unknown. The long-term goal of this work is to better understand the link between tau P301 mutations and memory impairment in FTD. The objective of this proposal is to determine the impact of mutant tau on translation. We will use human brain tissues as well as in vitro and in vivo models to study ribosomes in isolation, translation in cells, and brain pathophysiology in mice. Our preliminary results substantiate that the association between tau and ribosomal complexes impair protein synthesis. Therefore, the central hypothesis is that pathological tau inhibits translation of proteins critical for memory. The rationale for the proposed research is that understanding the tau-mediated mechanism of ribosomal dysfunction will aid in the design of therapeutic targets for FTD, which currently afflict a vast amount of individuals. Our strong preliminary data serves as support for testing the hypotheses that 1) pathological tau engages with different parts of the ribosome, 2) translational repression is present in various in vivo tau models. and 3) the ribosomes’ affinity for transcripts, capacity, and efficiency are impaired in human FTD brains. These aims have the potential of extrinsic merit to be used as screening tools for modulators of ribosomal function. Our approach is innovative because it incorporates novel assays, which offer excellent sensitivity that is not achievable by more traditional approaches. This work is significant because it departs from the status quo by testing a new mechanism in which translation dysfunction mediates tauopathic symptoms. 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.