Tau exon 10 inclusion by prpc through downregulating gsk3β activity

Laia Lidón, Laura Llaó-Hierro, Mario Nuvolone, Adriano Aguzzi, Jesús Ávila, Isidro Ferrer, José Antonio Del Río, Rosalina Gavín

Research output: Contribution to journalArticlepeer-review

Abstract

Tau protein is largely responsible for tauopathies, including Alzheimer’s disease (AD), where it accumulates in the brain as insoluble aggregates. Tau mRNA is regulated by alternative splicing, and inclusion or exclusion of exon 10 gives rise to the 3R and 4R isoforms respectively, whose balance is physiologically regulated. In this sense, one of the several factors that regulate alternative splicing of tau is GSK3β, whose activity is inhibited by the cellular prion protein (PrPC), which has different physiological functions in neuroprotection and neuronal differentiation. Moreover, a relationship between PrPC and tau expression levels has been reported during AD evolution. For this reason, in this study we aimed to analyze the role of PrPC and the implication of GSK3β in the regulation of tau exon 10 alternative splicing. We used AD human samples and mouse models of PrPC ablation and tau overexpression. In addition, we used primary neuronal cultures to develop functional studies. Our results revealed a paralleled association between PrPC expression and tau 4R isoforms in all models analyzed. In this sense, reduction or ablation of PrPC levels induces an increase in tau 3R/4R balance. More relevantly, our data points to GSK3β activity downstream from PrPC in this phenomenon. Our results indicate that PrPC plays a role in tau exon 10 inclusion through the inhibitory capacity of GSK3β.

Original languageEnglish
Article number5370
JournalInternational Journal of Molecular Sciences
Volume22
Issue number10
DOIs
Publication statusPublished - May 2 2021

Keywords

  • Alternative splicing
  • Alzheimer’s disease
  • Cellular prion protein
  • GSK3β
  • Microtubule-associated protein tau
  • Tauopathies

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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