TYK2 regulates tau levels, phosphorylation and aggregation in a tauopathy mouse model
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.
Authors
- Jiyoen Kim
- Huda Y. Zoghbi (ORCID: https://orcid.org/0000-0002-0700-3349)
- Cristian A. Lasagna‐Reeves (ORCID: https://orcid.org/0000-0002-5499-3082)
- Young Doo Kim (ORCID: https://orcid.org/0000-0003-3231-7371)
- Jun Young Sonn (ORCID: https://orcid.org/0000-0002-5114-8983)
- Dah‐eun Chloe Chung (ORCID: https://orcid.org/0000-0002-7476-6688)
- Bradley T. Hyman (ORCID: https://orcid.org/0000-0002-7959-9401)
- Bakhos Tadros
- David M. Holtzman (ORCID: https://orcid.org/0000-0002-3400-0856)
- Yan Hong Wei Liang
Institutions
- Howard Hughes Medical Institute (US)
- Harvard University (US)
- Baylor College of Medicine (US)
- Washington University in St. Louis (US)
- Massachusetts General Hospital (US)
- Neurological Research Institute (US)
- Hope Center for Neurological Disorders (US)
- Texas Children's Hospital (US)
- Baylor Genetics (US)
- Indiana University School of Medicine
- Indiana University – Purdue University Indianapolis (US)
Publication Details
- Journal
- Nature Neuroscience
- Published
- 2024-11-11
- DOI
- https://doi.org/10.1038/s41593-024-01777-2
- Citations
- 16
- Primary Topic
- Alzheimer's disease research and treatments
- Type
- article
- Field-Weighted Citation Impact
- 5.22
Funders
- Howard Hughes Medical Institute
- JPB Foundation
- Johns Hopkins University
- National Institutes of Health
- National Institute on Aging
- National Institute of Neurological Disorders and Stroke