PKD1-tau disulfide linkage promotes tau phosphorylation and tau accumulation in a tauopathy mouse model

Abnormal accumulation of the microtubule-interacting protein tau is a characteristic feature of numerous neurodegenerative disorders, including Alzheimer’s disease (AD). Oxidative stress, a pivotal factor in neurodegeneration, contributes to aberrant formation of insoluble tau aggregates and neurotoxicity through mechanisms largely unknown. In this study, we demonstrate that the activation of protein kinase D1 (PKD1) and the formation of a PKD1-tau disulfide linkage, which occur downstream of oxidative stress and upstream of tau phosphorylation, act as pathogenic mediators that confer the detrimental effects of oxidative stress on tau in tauopathies. In the brains of individuals with tauopathies and in the PS19 tauopathy mouse model, active PKD1 exhibits significant colocalization with phosphorylated tau. Utilizing mass spectrometry, we identified that PKD1 forms a disulfide linkage with tau at the cysteine residue 322, which promotes sustained catalytic activity of PKD1 on tau phosphorylation at the Ser262 and Ser356 sites, leading to increased tau stabilization. Our findings demonstrate that overexpression of kinase-active PKD1 intensifies tau phosphorylation and pathological accumulation in the hippocampus of young PS19 tau-transgenic mice. Conversely, the genetic deletion of PKD1 alleviates tau hyperphosphorylation and tau pathology in aged PS19 mice. Additionally, PKD1 deletion was found to diminish neuronal and synaptic loss, ameliorate cognitive deficits, and restore protein homeostasis related to synaptic functions in the PS19 tauopathy mouse model. In summary, we propose a novel PKD1-dependent redox mechanism that facilitates tau hyperphosphorylation and tau pathology, and reveal PKD1 to be a novel therapeutic target for AD and related tauopathies.