Summary: Scientists have discovered that the protein TYK2 modifies tau protein, leading to their concentration in the brain—a important characteristic of Alzheimer’s disorder and related illnesses. By reducing TYK2 action in animal models, scientists found tau formation was decreased, suggesting TYK2 antagonists could be a prospective medical road. Although more research is required to ensure the effects of TYK2 inhibitors on tau levels in people brains, the findings may eventually aid in preventing tau-induced toxicity.
Important Information:
- TYK2 modifies beta protein, making them resistant to biological certification, leading to accumulation.
- Increasing TYK2 action in animals reduced beta levels and brain dangerous aggregation.
- TYK2 inhibitors, previously tested for various circumstances, might be repurposed to maintain tau in Alzheimer’s.
Origin: 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 Biology, the study suggests that half restraining TYK2 could be a strategy to reduce tau degrees and poisoning.
” Many studies have shown that the formation of tau in neurons and parietal cells in the brain is a key characteristic of Alzheimer’s disease and at least 24 more neural diseases”, said initial author , Dr. Ji-Yoen Kim, associate professor of chemical and individual 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 research demonstrated that tau is chemically altered in disease, primarily by adding extra phosphate to the protein’s Tyrosine groups, and that these modifications are essential for 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.
The team’s investigation into how TYK2 transforms tau into a protein that aggregates and spreads to neighboring cells and accumulates in tangles inside cells, influencing the development of tau-driven neurodegeneration.
The researchers are the first to demonstrate that TYK2’s modifications to tau contribute to tau-mediated disease by studying human cells and animal models of tau-driven dementia.
According to Kim,” We discovered that TYK2 adds phosphate groups to tau at a particular location on the protein identified as Tyrosine 29.”
By preventing autophagy, a cellular process crucial for the removal of proteins, tau levels in human cells and mouse neurons are stabilized, according to Kim.
” Impervious to clearance, modified tau accumulates in the brain”.
The discovery that TYK2 increases tau aggregation suggested that modifying TYK2 might help regulate and mitigate tau aggregation. The team’s analysis revealed that partially lowering TYK2 in two mouse models would reduce tau levels and stop it from accumulating.
Our findings point to the possibility that partially inhibiting TYK2 might be a method to lessen 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.  ,
To investigate their potential effects on Alzheimer’s disease and tau-induced dementias, studies are needed to determine whether these inhibitors actually enter the brain and lower tau levels.
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 research in neurology and genetics
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. What modifications, however, lead to the transformation of soluble tau into insoluble aggregates? We’ve previously used genetic testing to identify tyrosine kinase 2 ( TYK2 ) as a potential tau levels regulator.
We verified this finding by verifying that TYK2 phosphorylates tau at tyrosine 29 ( Tyr29 ), promoting its stabilization and promoting its aggregation in human cells. We discovered that tau is blocked by autophagic clearance by TYK2-mediated Tyr29 phosphorylation.
In P301S tau-transgenic mice, we also demonstrate that the TYK2-mediated phosphorylation of Tyr29 promotes pathological tau accumulation. 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.
