Gene Therapy with Arginine Decarboxylase and the Regulation of Tau

Daniel Lee, PhD
University of South Florida (Tampa, FL)

Co-Principal Investigators

Maj-Linda Selenica, PhD
University of South Florida (Tampa, FL)
Year Awarded:
2015
Grant Duration:
July 1, 2015 to June 30, 2019
Disease:
Alzheimer's Disease
Award Amount:
$250,000
Grant Reference ID:
A2015504S
Award Type:
Standard
Award Region:
US Southeastern
Daniel Lee, PhD

Polyamine and Arginine Metabolism Impact Tauopathies

Summary

The tau protein stabilizes microtubules, but when it accumulates in Alzheimer’s disease, it contributes to neurodegeneration. Arginine decarboxylase is an enzyme that metabolizes the amino acid arginine to make molecules known as polyamines. We find that increasing other arginine metabolizing enzymes, such as arginase 1, decreases tau in the brains of mice. This proposal will identify how arginine decarboxylase regulates tau pathology. Overall, we will identify whether increasing arginine metabolizing enzymes and polyamines in the brains of mice impacts tau neuropathology. In this way we hope to begin to identify therapeutic strategies, biomarkers or targets around these pathways that may ultimately alleviate tau burden.

Details

Currently no disease modify agents exist on the market for Alzheimer’s disease (AD). One major hallmark includes tau neuropathology, which encompasses number of neurodegenerative disease (more than 15) collectively known as tauopathies. Strategies aimed at reducing tau burden include increasing clearance, targeting kinases, posttranslational modifications, reducing aggregation, and modifying inflammation.

The goal of this project is to identify whether increasing arginine-metabolizing enzymes and polyamine producing proteins in the brains of mice impacts tau neuropathology and behavioral outcomes. Metabolism of the semi essential amino acid, L-arginine, signifies a critical branch point affecting multiple biological processes. Arginine metabolism also shows considerable influence upon tau biology. In the brain, we find that several pathways that govern depletion of arginine and production of subsequent by-products, known as polyamines, regulate tau neuropathology, inflammation, and protein clearance. Using gene therapy approaches in tau transgenic mice, we will examine how various arginine metabolic pathways and their products in the brain impact the tau phenotype including neuropathology and cognition.

Molecules known as polyamines are an interesting products of arginine metabolism, and they appear to regulate aggregation-prone proteins, including tau. Polyamines represent an exciting new area of research in tauopathies: old molecules with new purposes. We find that polyamines affect the fate of tau directly, at the protein level, as well as at the cellular level and in animal models. We also hypothesize that the depletion of L-arginine remains partly responsible for some of the impact on the tau phenotype; therefore we synthesized a unique gene designed to deplete L-arginine without increasing polyamines. This gene would introduce a new metabolic pathway to regulate L-arginine to determine the impact on tau biology in mice.      

The aim of this research is to gain sufficient understanding of the relationships to identify a potential drug target within the complex of interacting pathways associated with arginine metabolism that might be used to combat tauopathies. The goal is to identify a viable target that could be drugged or induced to provide maximum benefit with respect to tauopathies and Alzheimer’s disease-like pathology, but minimal changes in a host of other body systems.

About the Researcher

Daniel C. Lee, PhD, is an assistant professor and founding faculty member (2010) at University of South Florida (USF) College of Pharmacy & Pharmaceutical sciences, USF Health Byrd Alzheimer’s Institute. Dr. Lee received his B.S. degree in chemistry in 1999 at Lincoln University, Pa., and his Ph.D. in Pharmaceutical Sciences in 2005 in a pharmacology/toxicology track at Florida A&M University College of Pharmacy and Pharmaceutical Sciences. His dissertation focused on lysosomal proteases and protease inhibitors in models of Parkinson’s disease. Dr. Lee did his postdoctoral work at the USF College of Medicine with Dave Morgan, PhD, and Marcia Gordon, PhD, which focused on novel therapies for Alzheimer’s disease models and the role of inflammation in tau and amyloid beta pathology. As a postdoctoral scholar, he received numerous accolades, including the USF Research Interdisciplinary Postdoctoral Scholar Outstanding Presentation Award, awarded three times (2007, 2008, and 2009), as well as seven travel awards to international conferences. He is a member of Society for Neuroscience and has served as a FASEB MARC peer mentor since 2006. His current research focuses on the impact of inflammation, arginine metabolism and polyamine biology during tauopathies and synucleinopathies. He is an award recipient of Alzheimer’s Association, Cure PSP, The Michael J. Fox Foundation for Parkinson’s Research, and BrightFocus Foundation.


"My career direction really started with my grandfather, a physician, who planted the seed of healthcare in our family. My father (Daniel Lee, Jr.) became a physician’s assistant; his brother served as a physician in the military; one of my sisters received her PhD in pharmacology and now works for U.S Food and Drug Administration; and the other received her doctorate in pharmacology.  There is an innate drive to find cures for these devastating diseases.

My grandfather, who’s also named Daniel Lee, also motivated my current research focus. He was diagnosed with Parkinson’s disease in 1998, while I was studying chemistry as an undergraduate, and that motivated me to pursue a doctorate in neuropharmacology. He was later diagnosed with Alzheimer’s disease, and this guided me toward an Alzheimer’s focus to study commonalties and differences between the two top neurodegenerative diseases."

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