Discovery of In Vivo Molecular Pathways Mediating Tau Induced Sleep and Circadian Disruption

Project: Research project

Project Details

Description

This proposal addresses the PRMRP FY21 Topic Area of Sleep Disorders and Restriction. Disrupted daily sleep-wake cycles is a prominent feature of multiple neurodegenerative diseases caused by the protein Tau, collectively called “tauopathies”, including traumatic brain injury (TBI), frontotemporal dementia (FTD), and Alzheimer’s disease (AD). These diseases are highly prevalent especially in military populations where TBI is a major risk factor for AD. Sleep disorders can exacerbate AD, forming a vicious cycle. A simple animal model of tauopathy that captures disordered sleep similar to that seen in people suffering from tauopathies. Disordered sleep is observed prior to the death of neurons, providing the opportunity to reverse the disease with early intervention. In this proposal, we take advantage of the fly, a very genetically malleable model organism, to identify key genes that are crucial to mediating the circadian behavioral disruption caused by Tau toxicity in the brain. Even though the fruit fly brain is anatomically different from the human brain, the molecular clock operates using the same principles. This innovative paradigm enables the functional screening of hundreds of individual genes for their role in mediating the toxic effects of Tau in live animals. This would be the first time that a genetic screen for human tauopathy is done using Tau-dependent behavior in animals. The identification of genes involved in Tau-dependent neuronal toxicity would provide novel insights into tauopathy disease mechanisms and aid in the development of therapeutic targets, which would benefit both military and civilian populations alike.
StatusActive
Effective start/end date4/1/223/31/24

Funding

  • U.S. Army Medical Research and Materiel Command (W81XWH2210217)

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