Determine Whether PIWIL and piRNAs are Dysregulated in Tau Transgenic Mice and Human Neurodegenerative Tauopathies

Wenyan Sun, PhD
University of Texas Health Science Center San Antonio (San Antonio, TX)

Mentors

Bess Frost, PhD
Year Awarded:
2019
Grant Duration:
July 1, 2019 to June 30, 2021
Disease:
Alzheimer's Disease
Award Amount:
$200,000
Grant Reference ID:
A2019223F
Award Type:
Postdoctoral Fellowship
Award Region:
US Southern
Wenyan Sun, PhD

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.

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.

About the Researcher

I started my graduate training in 2008 at Xi’an Jiaotong University in China, where I finished my master’s training from the School of Medicine, followed by a Ph.D. from the School of Life Science and Technology’s Institute of Mitochondrial Biology and Medicine. My graduate studies resulted in three first-author publications. I then began a postdoctoral fellow and lecturer position at Xi’an Jiaotong University, where I worked to determine how nutritional compounds regulate mitochondrial function and homeostasis in the brain in the context of hypertension. I was awarded three grants and published four first-author and one senior author publications. It was during this time that I developed a passion for the brain, and sought to broaden my knowledge and expertise in the field of neuroscience. In 2016, I joined the laboratory of Dr. Bess Frost as a postdoctoral fellow, where I seek to understand the fundamental cell biology underlying tau-induced neurotoxicity in neurodegenerative tauopathies. Using a Drosophila model of tauopathy, I have found that tau causes a reduction in small non-coding Piwi-interacting RNAs (piRNAs), which induces a toxic activation of transposable elements. I also identified transposable elements that are increased at the RNA level in human tauopathy. This work was published in Nature Neuroscience and featured as a “research highlight” in Nature Reviews Neurology in 2018. A major focus of my current work is to translate my findings from Drosophila to mouse and human tauopathy, with the ultimate goal of developing more effective therapeutics for Alzheimer’s disease and related tauopathies.

Personal Story

My interest in neuroscience began with my studies on how hypertension affects the brain. As hypertension is an age-related disorder, I began to think more carefully about physiological versus pathological brain aging. To increase my opportunities for training and career advancement, I began a search for a postdoctoral position in the United States. I wanted to be at the forefront of brain aging research, and thus sought opportunities in labs centered around innovative and novel aspects of neurodegenerative disease research, while maintaining a focus on the effects of “normal” brain aging. I found these opportunities at the Barshop Institute for Longevity and Aging Studies in the lab of Dr. Bess Frost.

My initial project involved investigating “jumping genes” and their small regulatory RNAs in fruit fly models of human Alzheimer’s disease and related tauopathies. Fruit flies are an excellent model for studying age-related human disorders, as their neurobiology is well conserved, they are amenable to sophisticated genetic manipulations that allow me to address issues of causality, and they live a much shorter lifespan than most vertebrate animal models. As I have worked with fruit flies to learn more about underlying biology of tauopathies like Alzheimer’s disease, my curiosity about neurodegenerative diseases has grown exponentially, and I have expanded my studies to include mouse and human samples. As my studies progress, I will identify additional new drug targets for future therapeutic development.

Throughout my postdoctoral training, I have enjoyed the discovery, challenges, and collaboration that are vital to scientific inquiry. I am particularly grateful to have access to precious human brain samples with which to do my research. My work illustrates how donation of tissues from donors helps to translate research from animal models to humans. I greatly appreciate the gift from brain donors and their families and strive to do my best in my studies so that their contributions are meaningful and lead to a greater understanding of human neurodegenerative disorders.

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