Researchers at Baylor College of Medicine, the Jan Duncan Neurological Institute (Duncan NRI) at Texas Children’s Hospital, and collaborating institutions found that the enzyme TYK2 converts the normal protein tau into a protein that accumulates in the brain, contributing to the development of Alzheimer’s disease. It was discovered that it contributed to Disease in animal models. The study, published in Nature Neuroscience, suggests that partially inhibiting TYK2 may be a strategy to reduce tau levels and toxicity.
“A number of studies have shown that tau accumulation in neurons and glial cells in the brain is a key feature of Alzheimer’s disease and at least 24 neurological diseases,” said lead author and assistant professor of molecular and human sciences. said Dr. Jiyoung Kim. He studies genetics in Dr. Huda Zoghbi’s lab at Baylor. Zoghbi, the paper’s corresponding author, is a Distinguished Service Professor at Baylor University, director of the Duncan NRI, and a Howard Hughes Medical Institute (HHMI) investigator.
Previous studies have shown that tau is chemically modified in diseases, primarily by the addition of extra phosphates to protein tyrosine groups, and that these changes play an important role in regulating tau accumulation. are.
The Zoghbi lab had previously identified TYK2, an enzyme that adds phosphate to tyrosine groups, as a potential regulator of tau levels, and that knocking down the TYK2 gene reduced tau levels in human cells. . In this study, the research team investigated how TYK2 converts tau into a protein that aggregates and propagates to neighboring cells, tangles and accumulates within the cell, and influences the progression of tau-induced neurodegeneration. We dug deeper to find out how to provide the best results.
Using human cell and animal models of tau-induced dementia, researchers showed for the first time that TYK2 modifications to tau contribute to tau-mediated disease. “We discovered that TYK2 adds a phosphate group to tau at a specific position on the protein identified as tyrosine 29,” Kim said. “This modification stabilizes tau levels in human cells and mouse neurons by rendering them resistant to autophagy, an important cellular process for removing proteins,” Kim said. “Modified tau accumulates in the brain without being affected by clearance.”
The finding that TYK2 promotes tau aggregation suggested that manipulation of TYK2 may help regulate tau aggregation and its consequences. The research team tested the effect of partially reducing TYK2 in two mouse models and found that this was sufficient to reduce tau levels and alleviate its accumulation. “Although more research is needed, our findings suggest that partial inhibition of TYK2 may be a strategy to reduce tau accumulation and toxicity,” Kim said.
To this end, we are encouraged by the fact that other researchers have developed TYK2 inhibitors and are being tested in humans for other indications. Studies are needed to determine whether these inhibitors actually enter the brain and reduce tau levels to investigate potential effects in Alzheimer’s disease and tau-induced dementia. ”
Dr. Huda Zoghbi, corresponding author
Bakos Tadros, Hong Liang Yang, Yongdu Kim, Christian Lasagna-Reeves, Jun Yong Song, Daun Chloe Chan, Bradley Hyman, and David M. Holzman also contributed to this work. The authors are affiliated with one or more of the following institutions: Baylor College of Medicine, the Jean and Dan Duncan Neurological Institute at Texas Children’s Hospital, Indiana University School of Medicine, Harvard Medical School, and Washington University Massachusetts General Hospital in St. Louis; Howard Hughes Medical Institute.
This research was funded by the JPB Foundation, HHMI, Eunice Kennedy Shriver National Institute of Child Health and Human Development NIH grant P50HD103555 and NIH/NINDS grant R01NS119280.
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Baylor College of Medicine
Reference magazines:
Kim, J. et al. (2024). TYK2 controls tau levels, phosphorylation, and aggregation in tauopathy mouse models. Natural neuroscience. doi.org/10.1038/s41593-024-01777-2.
