Phospho-Tau Signature During Mitosis: AT8, p-T217 and p-S422 as Key Phospho-Epitopes

TL;DR

This study identifies specific phosphorylation sites on Tau during cell division, offering insights into how Tau behaves in normal and disease conditions.

Contribution

The study establishes a mitotic phospho-Tau signature, highlighting AT8, p-T217, and p-S422 as key epitopes phosphorylated during mitosis.

Findings

Tau is highly phosphorylated at AT8, p-T217, and p-S422 during mitosis in vitro and in vivo.

Mitotic Tau phosphorylation resembles pathological hyperphosphorylation observed in tauopathies.

The findings reveal a potential link between physiological and pathological Tau phosphorylation.

Abstract

Tau was initially identified as a microtubule-binding protein critical for microtubule stabilization. It is also a pathological hallmark of tauopathies, a group of neurodegenerative diseases that include Alzheimer’s disease. Under pathological conditions, Tau becomes hyperphosphorylated at numerous sites and aggregates into filamentous deposits, contributing to neuronal cell death and disease progression. While significant research has focused on Tau phosphorylation dynamics and their consequences in pathological contexts, comparatively few studies have investigated Tau phosphorylation during physiological processes, despite the potential relevance to the early onset of pathology. Previous findings have suggested similarities between mitotic Tau phosphorylation and hyperphosphorylation observed in tauopathies, particularly at sites such as AT8, PHF1, S214, and S422. In this study, we quantified the relative levels of phosphorylation at 12 Tau phospho-epitopes during interphase and mitosis in vitro to establish a preliminary mitotic phospho-Tau signature, which was subsequently validated in vivo. Our results demonstrated pronounced phosphorylation of Tau at AT8, p-T217, and p-S422 epitopes during mitosis, both in vitro and in vivo. These findings provide new insights into the physiological phosphorylation of Tau and its potential links to pathological processes.

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