Alzheimer’s disease: Ablating single master site abolishes tau hyperphosphorylation

Kristie Stefanoska, Arne Ittner, Mehul Gajwani, Amanda RP Tan, Holly Ahel, Prita Asih, Alexander Volkerling & Anne Poljak
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...
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