Researchers from The University of Texas San Antonio Health Sciences Center (UT Health San Antonio) today announced the discovery of a new mechanism by which diseased forms of tau cause neuron death. Alzheimer’s disease and chronic traumatic encephalopathy (CTE) are among more than 20 disorders that include tau pathology.
The newly discovered mechanism of tau-induced damage can be altered pharmacologically, the scientists noted, making it a novel target for drug development.
The study, published in Alzheimer’s and dementia: the journal of the Alzheimer’s Association, “provides a framework for future studies in vertebrate models of tauopathy and possibly clinical trials in humans,” said first author Gabrielle Zuniga. Zuniga is a MD/PhD student in the South Texas Medical Scientist Training Program offered jointly by the Joe R. and Teresa Lozano Long School of Medicine and the Graduate School of Biomedical Sciences at UT Health San Antonio.
“The fact that it’s a drug target is really exciting, and it’s a new mechanism that hasn’t been established before,” Zuniga said.
An early event, before the death of neurons
Working with a fruit fly that expresses mutant human tau, the scientists observed deficits in an RNA quality control pathway known as nonsense-mediated mRNA decay. “It’s an early event,” Zuniga said. “These changes in RNA quality control occurred long before neuronal cell death.”
“Nonsense-mediated mRNA decay is a key step in the process by which genetic information is translated into proteins,” Zuniga said. Impairment of this quality control mechanism results in accumulations of RNA and the production of abnormal and dysfunctional proteins. “It has an absolutely detrimental effect,” Zuniga said.
DNA (a molecule called deoxyribonucleic acid) contains the genetic blueprints for proteins. Messenger RNA (ribonucleic acid) reads blueprints to make proteins. This information highway becomes blocked when nonsense-induced mRNA decay is reduced.
“We are focusing on how cells eliminate faulty RNAs and how this RNA quality control mechanism becomes disrupted in disease. If these types of RNA accumulate in a cell and are translated into proteins, bad things can happen,” said lead author Bess Frost, PhD, Bartell Zachry Distinguished Professor for Research in Neurodegenerative Disorders at UT Health San Antonio . Dr. Frost, Associate Professor of Cellular Systems and Anatomy, is a Fellow of the Sam and Ann Barshop Institute for Longevity and Aging Studies at the Health Sciences Center and the Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases.
Go beyond the tau deposit
Treatments for Alzheimer’s disease and other tauopathies have failed in part because they focus on eliminating tau or another protein called beta-amyloid. Beta-amyloid plaques and tau tangles are classic hallmarks of Alzheimer’s disease.
“Rather than targeting tau deposition, which is late in the disease process, why not shut down the pathways that actually cause neuron death?” said Sudha Seshadri, MD, professor of neurology at the Long School of Medicine and founding director of the Glenn Biggs Institute. “This appears to be one of those pathways, and its discovery is brilliant detective work by Gabrielle Zuniga, Dr. Frost and team.”
Dr. Seshadri and Dr. Frost are researchers at the South Texas Alzheimer’s Disease Research Center, a recently awarded Center of Excellence from the National Institutes of Health, which is a partnership between UT Health San Antonio and UT Rio Grande Valley. It is the only designated Alzheimer’s disease research center in Texas.
Identifying multiple mechanisms underlying tau (and beta-amyloid) pathology could provide insight into which patients might benefit from which therapies, said Nicolas Musi, MD, professor of medicine at UT Health San Antonio and director of the Sam and Ann Barshop Institute. A subset of Alzheimer’s disease patients might be sensitive to a drug that increases nonsense-mediated mRNA degradation, for example.
First author Zuniga completed two years at the Long School of Medicine before embarking on her doctoral studies in philosophy. She is a candidate in June for her doctorate and will return to medical school in the fall for the third and fourth years of her journey to become a doctor. Originally from Chapel Hill, North Carolina, she graduated in 2015 from the University of Texas at Austin.
“Gabbe exemplifies the genius of our MSTP students who embark on this ambitious dual-degree academic medical path and who are determined to serve humanity by conducting rigorous translational research that improves lives,” said Jose E. Cavazos, MD. , PhD, professor of neurology and assistant dean of the South Texas Medical Scientist Training Program (MSTP).
Reference: Zuniga G, Levy S, Ramirez P, et al. Tau-induced deficits in nonsense-mediated mRNA decay contribute to neurodegeneration. Alzheimers. Dementia. 2022.doi:10.1002/alz.12653
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