Teravskis PJ, Oxnard BR, Miller EC, Kemper L, Ashe KH, Liao D. Phosphorylation in Two Discrete Tau Domains Regulates a Stepwise Process Leading to Postsynaptic Dysfunction. Journal of Physiology. 2019;597:2483-2498. PMID: 30714637. DOI: 10.1113/JP277696.
Summary
This study dissected how tau phosphorylation controls tau mislocalization and postsynaptic dysfunction. The authors found that phosphorylation in the C-terminal domain promotes tau movement into dendritic spines, whereas phosphorylation in the proline-rich region is required for postsynaptic impairment. These results support a stepwise model in which different tau modifications regulate distinct phases of synaptic toxicity. The work clarifies how tau phosphorylation interacts with tau localization and functional synaptic decline.
Key Findings
- C-terminal tau phosphorylation promoted dendritic spine localization.
- Proline-rich region phosphorylation was linked to postsynaptic dysfunction.
- Tau mislocalization and synaptic impairment were separable events.
- Multiple kinases contributed to tau-dependent synaptic pathology.
Impact on the Caspase-2/Tau Program
This paper refined the mechanistic context for tau synaptotoxicity. It supports the broader therapeutic rationale that specific tau species and modifications, rather than total tau burden alone, drive functional impairment.