Alzheimer’s disease: Ablating single master site abolishes tau hyperphosphorylation
Cite this dataset
Stefanoska, Kristie et al. (2022). Alzheimer’s disease: Ablating single master site abolishes tau hyperphosphorylation [Dataset]. Dryad. https://doi.org/10.5061/dryad.bvq83bkc0
Hyperphosphorylation of the neuronal tau protein is a hallmark of neurodegenerative tauopathies such as Alzheimer’s disease. A central unanswered question is why tau becomes progressively hyperphosphorylated. Here, we show that tau phosphorylation is governed by interdependence— a mechanistic link between initial site-specific and subsequent multi-site phosphorylation. Systematic assessment of site interdependence identified distinct residues (threonine-50, threonine-69, and threonine-181) as master sites that determine propagation of phosphorylation at multiple epitopes. CRISPR point mutation and expression of human tau in Alzheimer’s mice showed that site interdependence governs physiologic and amyloid-associated multi-site phosphorylation and cognitive deficits, respectively. Combined targeting of master sites and p38α, the most central tau kinase linked to interdependence, synergistically ablated hyperphosphorylation. In summary, our work delineates how complex tau phosphorylation arises to inform therapeutic and biomarker design for tauopathies.
Raw Immunoblot data for Figure 1. Chemiluninescence signals were imaged on a ChemiDoc MP (Biorad) digital system.
Alzheimer's Australia Dementia Research Foundation
National Health and Medical Research Council, Award: 1143978
National Health and Medical Research Council, Award: 1176628
Australian Research Council, Award: DP170100843
Australian Research Council, Award: DP200102396
Australian Research Council, Award: DP220101900
BrightFocus Foundation, Award: A2022022F