Considerable evidence suggests that phosphorylation of tau at tyrosine residues plays a part in tau-mediated neurodegeneration. However, the modifications involved in conversion from soluble to insoluble tau remain unclear, in part because tau has five tyrosine residues that can all be phosphorylated. Now, Kim et al. report that TYK2 phosphorylates tau at Tyr29, which promotes the accumulation of insoluble tau in neurofibrillary tangles (NFTs) — a neuropathological feature of several neurodegenerative diseases.

In human neuroblastoma cells and cultured primary neurons, Kim et al. first found that inhibition of TYK2 activity with deucravacitinib or knockdown of TYK2 levels with a short hairpin RNA (shRNA) led to reduced levels of endogenous tau, whereas TYK2 overexpression led to increased endogenous tau levels in both cell types. In line with these results, the brains of wild-type mice injected with recombinant adenovirus containing Tyk2 shRNA (which knocked down TYK2 levels by 40–50%) showed a 25% reduction in endogenous tau levels compared with untreated mouse brains. Studies in several mouse models confirmed that most of this reduction occurred in neurons.