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

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.

Grant Number: 5R01AG075900-05
NIH Institute/Center: NIH
Principal Investigator: Jose Abisambra