TYK2 regulates tau levels, phosphorylation and aggregation in a tauopathy mouse model

Jiyoen Kim; Bakhos Tadros; Yan Hong Liang; Youngdoo Kim; Cristian Lasagna-Reeves; Jun Young Sonn; Dah-Eun Chloe Chung; Bradley Hyman; David M Holtzman; Huda Yahya Zoghbi

doi:10.1038/s41593-024-01777-2

TYK2 regulates tau levels, phosphorylation and aggregation in a tauopathy mouse model

Nat Neurosci. 2024 Nov 11. doi: 10.1038/s41593-024-01777-2. Online ahead of print.

Authors

Jiyoen Kim^{1

2}, Bakhos Tadros^{1

2}, Yan Hong Liang^{1

2}, Youngdoo Kim^{1

2}, Cristian Lasagna-Reeves³, Jun Young Sonn^{1

2}, Dah-Eun Chloe Chung^{1

2}, Bradley Hyman⁴, David M Holtzman⁵, Huda Yahya Zoghbi^{6

7

8

9}

Affiliations

¹ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
² Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX, USA.
³ Stark Neurosciences Research Institute and Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, IN, USA.
⁴ Neurology at Harvard Medical School and Massachusetts General Hospital, Boston, MA, USA.
⁵ Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimers' Disease Research Center, Washington University in St. Louis, St. Louis, MO, USA.
⁶ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. [email protected].
⁷ Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX, USA. [email protected].
⁸ Departments of Neuroscience, Pediatrics, and Neurology, Baylor College of Medicine, Houston, TX, USA. [email protected].
⁹ Howard Hughes Medical Institute, Chevy Chase, MD, USA. [email protected].

PMID: 39528671
DOI: 10.1038/s41593-024-01777-2

Abstract

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.

Abstract

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