Investigating PIWIL and piRNAs in Tau Transgenic Mice and Human Tauopathy

Summary

I recently identified depletion of Piwi/piRNAs-induced aberrant transposable element activation as a pharmacologically targetable, mechanistic driver of neurotoxicity in tau transgenic Drosophila. Since I reported that aberrant transposable element transcription is conserved in human tauopathy, I next determine whether machinery of transposable element silencing mediated by PIWIL and piRNAs is dysfunctional in tau transgenic mice. I will further determine if piRNAs that identified in Alzheimer’s disease are directly bound to PIWIL and determine if they are relevant to human tauopathy. If our hypothesis is correct, dysregulated PIWIL/piRNAs will be a potential pharmacological target of reverse transcriptase inhibitor (3TC) to suppress transposable element expression and consequent neurotoxicity on tau transgenic mice and future clinical trials on Alzheimer’s disease.

Note: This grant was terminated by the investigator on February 28, 2021, when she left the University of Texas Health Science Center San Antonio for an industry position.

Project Details

The goal of my project is to better understand the contribution of small regulatory RNAs, termed piwi-interacting RNAs (piRNAs), to brain cell death in Alzheimer’s disease and related tauopathies.  

Tauopathies are a group of age-related neurodegenerative disorders, including Alzheimer’s disease, that involve accumulation of tau protein in the brain of affected individuals. There are currently no effective, disease-modifying therapies for tauopathies. I have recently used fruit fly models of tauopathy to identify a novel mechanism of tau-mediated neurotoxicity that involves piRNAs and the jumping genes that they silence. Importantly, I found that tau-induced jumping gene activation is amenable to pharmacological intervention. Using the knowledge gained from the fruit fly regarding the relationship between tau, piRNAs, jumping genes, and brain cell death, I am currently extending my studies to mouse models of tauopathy as well as human brain tissue from patients affected by tauopathy. My first goal is to determine if the cellular machinery that regulates piRNAs changes with “normal” brain aging and if piRNA dysregulation can be reversed by clearing pathological tau from the mouse brain. My second goal is to identify bona fide piRNAs in the human brain, and to determine if they are differentially regulated in human Alzheimer’s disease and progressive supranuclear palsy (a “primary” tauopathy) versus age-matched control brains.

I am investigating a novel, pharmacologically targetable mechanism of brain cell death in Alzheimer’s disease and related tauopathies. An innovative aspect of my studies is the multi-system approach that I apply to the study of neurodegenerative disease. I utilize fruit flies for early discovery, which inform and help shape my subsequent studies in mouse and human tauopathy. As we currently know little regarding the basic biology of how piRNAs are regulated in the brain and change with normal brain aging, my project will also generate new knowledge in regard to brain aging, neurodegeneration, and piRNA regulation.  

I have reported that Lamivudine, a reverse transcriptase inhibitor that is FDA-approved for HIV and Hepatitis B, blocks the jumping of jumping genes and increases brain cell survival in the fruit fly model of human tauopathy. The studies funded by BrightFocus will allow me to determine if my findings in fruit flies are relevant to human disease, which will set the stage for future therapeutic development of reverse transcriptase inhibitors and/or drugs that elevate piRNA levels for tauopathy patients.