[R21] The impact of tau on RNA and translation in progressive supranuclear palsy
Ente: National Institute on Aging
Scadenza: 2028-05-31
Importo max: 422.125 EUR
Paese: US
Descrizione
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.
Istituzione: UNIVERSITY OF FLORIDA
PI: Jose Francisco Abisambra
Progetto: 1R21AG095654-01
Settori: National Institute on Aging
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