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Phosphorylation of microtubule-associated protein tau by AMPK-related kinases

Hirotaka Yoshida1, Michel Goedert

  • 1MRC Laboratory of Molecular Biology, Cambridge, UK. hiro@mrc-lmb.cam.ac.uk

Journal of Neurochemistry
|October 12, 2011
PubMed

Insights

AMPK-related kinases, including MARK1 and SIK, phosphorylate tau protein at specific sites (S262/S356). Inhibiting these kinases reduces tau phosphorylation, offering potential therapeutic targets for tauopathies like Alzheimer's disease.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Biochemistry

Background:

  • Abnormal tau hyperphosphorylation is a hallmark of neurodegenerative diseases, including Alzheimer's disease and tauopathies.
  • Microtubule-associated protein/microtubule-affinity regulating kinases (MARKs) are known to phosphorylate tau at KxGS motifs.

Purpose of the Study:

  • To investigate the role of various AMPK-related kinases in tau phosphorylation.
  • To determine if MARK1 and SIK contribute significantly to tau phosphorylation at specific sites.

Main Methods:

  • Assessed the tau-phosphorylating activity of AMPK-related kinases: BSks1/2, MELK, MARK1, and SIK.
  • Utilized antibody 12E8 to detect phosphorylation at S262 and S356.
  • Examined the effect of kinase down-regulation and BX 795 (MARK1/SIK inhibitor) on tau phosphorylation in rat cortical neurons.

Main Results:

  • MARK1 and SIK demonstrated the most effective phosphorylation of tau.
  • Down-regulation of MARK1 and SIK led to decreased 12E8-labelling of tau.
  • BX 795 treatment reduced 12E8-immunolabelling of tau in neuronal cultures.

Conclusions:

  • AMPK-related kinases, particularly MARK1 and SIK, play a significant role in tau phosphorylation at S262/S356.
  • These findings highlight a potential therapeutic avenue for tauopathies by targeting these kinases.

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