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Cytoplasmic SET induces tau hyperphosphorylation through a decrease of methylated phosphatase 2A

Stéphanie Chasseigneaux, Christine Clamagirand, Léa Huguet

  • 1INSERM UMR 894, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France. bernadette.allinquant@inserm.fr.

BMC Neuroscience
|July 2, 2014
PubMed
Abstract

Insights

SET protein in neuronal cytoplasm causes tau hyperphosphorylation, a key Alzheimer's disease event. This cytoplasmic SET impairs phosphatase 2A (PP2A) activity, linking it to Alzheimer's pathogenesis.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Biochemistry

Background:

  • SET, an inhibitor of phosphatase 2A (PP2A), is found in the neuronal cytoplasm in Alzheimer's disease (AD) brains.
  • Its cytoplasmic localization is linked to tau hyperphosphorylation, a hallmark of AD, but the underlying mechanisms remain unclear.

Purpose of the Study:

  • To elucidate the role of SET's neuronal cytoplasmic localization in tau hyperphosphorylation.
  • To investigate the impact of cytoplasmic SET on PP2A activity and methylation.
  • To establish the link between SET translocation, PP2A dysfunction, and AD pathogenesis.

Main Methods:

  • Experiments using primary neurons and mouse brain slices.
  • Investigating SET translocation, cleavage, and overexpression.
  • Assessing tau phosphorylation levels (Ser-202, Ser-422) and PP2A activity/methylation.

Main Results:

  • SET translocation to the cytoplasm, independent of cleavage or overexpression, induces tau hyperphosphorylation.
  • Cytoplasmic SET reduces PP2A activity by decreasing methylated PP2A levels.
  • Decreased methylated PP2A levels correlate with tau hyperphosphorylation at Ser-202.

Conclusions:

  • Neuronal cytoplasmic localization of full-length SET is sufficient to impair PP2A methylation and activity, causing tau hyperphosphorylation.
  • This SET-induced cascade, involving decreased PP2A activity and tau hyperphosphorylation, contributes to Alzheimer's disease pathogenesis.
  • Distinct mechanisms may regulate tau phosphorylation at different sites.

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