Publication Date
12-1-2024
Journal
Nature Neuroscience
DOI
10.1038/s41593-024-01777-2
PMID
39528671
PMCID
PMC11614740
PubMedCentral® Posted Date
11-11-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Animals, tau Proteins, TYK2 Kinase, Phosphorylation, Tauopathies, Mice, Transgenic, Humans, Mice, Disease Models, Animal, Protein Aggregation, Pathological, Molecular neuroscience, Phosphorylation, Alzheimer's disease
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.
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