Targeting Enzyme TYK2 Could Reduce Tau in Alzheimer’s Disease

Summary: Scientists have discovered that the enzyme TYK2 modifies tau proteins, leading to their accumulation in the brain—a key feature of Alzheimer’s disease and related dementias. By reducing TYK2 activity in animal models, researchers found tau buildup was decreased, suggesting TYK2 inhibitors could be a potential therapeutic pathway. The findings could eventually help prevent tau-induced toxicity, although more research is needed to confirm TYK2 inhibitors’ effects on tau levels in human brains.

Key Facts:

  • TYK2 modifies tau proteins, making them resistant to cellular clearance, leading to accumulation.
  • Lowering TYK2 activity in mice reduced tau levels and its toxic aggregation in the brain.
  • TYK2 inhibitors, already tested for other conditions, might be repurposed to manage tau in Alzheimer’s.

Source: Baylor College of Medicine

Researchers at Baylor College of Medicine, the Jan and Dan Duncan Neurological Research Institute (Duncan NRI) at Texas Children’s Hospital and collaborating institutions discovered that the enzyme TYK2 transforms the normal protein tau into one that accumulates in the brain and contributes to the development of Alzheimer’s disease in animal models.

Published in Nature Neuroscience, the study suggests that partially restraining TYK2 could be a strategy to reduce tau levels and toxicity.

This shows tau.
Previous studies showed that tau is chemically modified in disease, predominantly by the addition of extra phosphate to the Tyrosine groups in the protein, and that these changes play a crucial role in regulating tau accumulation. Credit: Neuroscience News

“Many studies have shown that the accumulation of tau in neurons and glial cells in the brain is a main characteristic of Alzheimer’s disease and at least 24 more neurological diseases,” said first author Dr. Ji-Yoen Kim, assistant professor of molecular and human genetics at Baylor in the lab of Dr. Huda Zoghbi.

Zoghbi, the corresponding author of the work, is a Distinguished Service Professor at Baylor, director of the Duncan NRI and a Howard Hughes Medical Institute (HHMI) investigator.

Previous studies showed that tau is chemically modified in disease, predominantly by the addition of extra phosphate to the Tyrosine groups in the protein, and that these changes play a crucial role in regulating tau accumulation.

The Zoghbi lab had earlier 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 the current study, the team dug deeper into how TYK2 transforms tau into a protein that aggregates and propagates to neighboring cells and accumulates in tangles inside cells, influencing the development of tau-driven neurodegeneration.

Working with human cells and animal models of tau-driven dementia, the researchers are the first to show that TYK2’s modifications to tau contribute to tau-mediated disease.

“We found that TYK2 adds phosphate groups to tau at a particular location on the protein identified as Tyrosine 29,” Kim said.

“This modification stabilizes tau levels in human cells and mouse neurons by making it resistant to autophagy, a cellular process important for clearing proteins,” Kim said.

“Impervious to clearance, modified tau accumulates in the brain.”

The finding that TYK2 enhances the aggregation of tau suggested that manipulating TYK2 might help regulate tau aggregation and its consequences. The team tested the effect of partially reducing TYK2 in two mouse models and found that this was sufficient to reduce tau levels and mitigate its accumulation.

“Although much work is needed, our findings suggest that partial inhibition of TYK2 could thus be a strategy to reduce tau accumulation and toxicity,” Kim said.

“To this end, we are encouraged by the fact that others have developed TYK2 inhibitors that have been tested in humans for other indications,” said Zoghbi. 

“Studies are needed to see if these inhibitors indeed get into the brain and lower tau levels to explore their potential effects in Alzheimer’s disease and tau-induced dementias.” 

Bakhos Tadros, Yan Hong Liang, Youngdoo Kim, Cristian Lasagna-Reeves, Jun Young Sonn, Dah-eun Chloe Chung, Bradley Hyman and David M. Holtzman also contributed to this work. The authors are affiliated with one or more of the following institutions: Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Indiana University School of Medicine, Harvard Medical School and Massachusetts General Hospital, Washington University in St. Louis and Howard Hughes Medical Institute.

Funding: This work was funded by JPB Foundation, HHMI, Eunice Kennedy Shriver National Institute of Child Health and Human Development NIH grant P50HD103555 and NIH/NINDS grant R01NS119280.

About this genetics and neurology research news

Author: Graciela Gutierrez
Source: Baylor College of Medicine
Contact: Graciela Gutierrez – Baylor College of Medicine
Image: The image is credited to Neuroscience News

Original Research: Open access.
TYK2 regulates of tau levels, phosphorylation, and aggregation in tauopathy model mice” by Ji-Yoen Kim et al. Nature Neuroscience


Abstract

TYK2 regulates of tau levels, phosphorylation, and aggregation in tauopathy model mice

Alzheimer’s disease is one of at least 26 diseases characterized by tau-positive accumulation in neurons, glia or both. However, it is still unclear what modifications cause soluble tau to transform into insoluble aggregates. We previously performed genetic screens that identified tyrosine kinase 2 (TYK2) as a candidate regulator of tau levels.

Here we verified this finding and found that TYK2 phosphorylates tau at tyrosine 29 (Tyr29) leading to its stabilization and promoting its aggregation in human cells. We discovered that TYK2-mediated Tyr29 phosphorylation interferes with autophagic clearance of tau.

We also show that TYK2-mediated phosphorylation of Tyr29 facilitates pathological tau accumulation in P301S tau-transgenic mice. Furthermore, knockdown of Tyk2 reduced total tau and pathogenic tau levels and rescued gliosis in a tauopathy mouse model.

Collectively, these data suggest that partial inhibition of TYK2 could thus be a strategy to reduce tau levels and toxicity.

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