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C-terminal truncation of GSK-3β enhances its dephosphorylation by PP2A

Nana Jin1, Yue Wu1, Wen Xu1,2

  • 1Key laboratory of neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Regeneration, Nantong University, China.

FEBS Letters
|March 8, 2017
PubMed

Insights

Truncation of glycogen synthase kinase-3β (GSK-3β) by calpain I in Alzheimer's disease (AD) brains reduces its Ser9 phosphorylation. This dephosphorylation enhances GSK-3β activity, potentially contributing to tau pathology.

Area of Science:

  • Neuroscience
  • Biochemistry
  • Pathology

Background:

  • Glycogen synthase kinase-3β (GSK-3β) is a key enzyme in tau protein phosphorylation.
  • In Alzheimer's disease (AD), GSK-3β is truncated by calpain I, increasing its activity.
  • The impact of this truncation on GSK-3β phosphorylation remains unclear.

Purpose of the Study:

  • To investigate the effect of C-terminal truncation on GSK-3β phosphorylation at Ser9.
  • To elucidate the mechanism by which truncated GSK-3β activity is regulated in AD.
  • To explore the role of the calpain-GSK-3β-protein phosphatase 2A (PP2A) pathway in AD tau pathogenesis.

Main Methods:

  • Analysis of GSK-3β phosphorylation at Ser9 in AD brain samples and cultured cells.
  • Investigation of GSK-3β nuclear translocation and interaction with PP2A.
  • Assessment of the impact of C-terminal truncation on GSK-3β activity and PP2A-mediated dephosphorylation.

Main Results:

  • C-terminally truncated GSK-3β exhibits reduced Ser9 phosphorylation compared to full-length GSK-3β in AD brains and cell cultures.
  • Truncation facilitates GSK-3β nuclear translocation and enhances its binding to PP2A.
  • PP2A-mediated dephosphorylation of truncated GSK-3β leads to increased enzyme activity.

Conclusions:

  • GSK-3β truncation by calpain I in AD brains results in decreased Ser9 phosphorylation.
  • This dephosphorylation, mediated by enhanced PP2A interaction, likely contributes to increased GSK-3β activity.
  • The calpain-GSK-3β-PP2A axis represents a significant pathway in the tau pathology of Alzheimer's disease.
Keywords:
Alzheimer's diseaseglycogen synthase kinase-3βphosphorylationprotein phosphatase 2Atruncation

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