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Tau Exon 10 Inclusion by PrP(C) through Downregulating GSK3β Activity

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...

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Autores principales: Lidón, Laia, Llaó-Hierro, Laura, Nuvolone, Mario, Aguzzi, Adriano, Ávila, Jesús, Ferrer, Isidro, del Río, José Antonio, Gavín, Rosalina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8161268/
https://www.ncbi.nlm.nih.gov/pubmed/34065232
http://dx.doi.org/10.3390/ijms22105370
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author Lidón, Laia
Llaó-Hierro, Laura
Nuvolone, Mario
Aguzzi, Adriano
Ávila, Jesús
Ferrer, Isidro
del Río, José Antonio
Gavín, Rosalina
author_facet Lidón, Laia
Llaó-Hierro, Laura
Nuvolone, Mario
Aguzzi, Adriano
Ávila, Jesús
Ferrer, Isidro
del Río, José Antonio
Gavín, Rosalina
author_sort Lidón, Laia
collection PubMed
description 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 (PrP(C)), which has different physiological functions in neuroprotection and neuronal differentiation. Moreover, a relationship between PrP(C) and tau expression levels has been reported during AD evolution. For this reason, in this study we aimed to analyze the role of PrP(C) and the implication of GSK3β in the regulation of tau exon 10 alternative splicing. We used AD human samples and mouse models of PrP(C) ablation and tau overexpression. In addition, we used primary neuronal cultures to develop functional studies. Our results revealed a paralleled association between PrP(C) expression and tau 4R isoforms in all models analyzed. In this sense, reduction or ablation of PrP(C) levels induces an increase in tau 3R/4R balance. More relevantly, our data points to GSK3β activity downstream from PrP(C) in this phenomenon. Our results indicate that PrP(C) plays a role in tau exon 10 inclusion through the inhibitory capacity of GSK3β.
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spelling pubmed-81612682021-05-29 Tau Exon 10 Inclusion by PrP(C) through Downregulating GSK3β Activity Lidón, Laia Llaó-Hierro, Laura Nuvolone, Mario Aguzzi, Adriano Ávila, Jesús Ferrer, Isidro del Río, José Antonio Gavín, Rosalina Int J Mol Sci Article 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 (PrP(C)), which has different physiological functions in neuroprotection and neuronal differentiation. Moreover, a relationship between PrP(C) and tau expression levels has been reported during AD evolution. For this reason, in this study we aimed to analyze the role of PrP(C) and the implication of GSK3β in the regulation of tau exon 10 alternative splicing. We used AD human samples and mouse models of PrP(C) ablation and tau overexpression. In addition, we used primary neuronal cultures to develop functional studies. Our results revealed a paralleled association between PrP(C) expression and tau 4R isoforms in all models analyzed. In this sense, reduction or ablation of PrP(C) levels induces an increase in tau 3R/4R balance. More relevantly, our data points to GSK3β activity downstream from PrP(C) in this phenomenon. Our results indicate that PrP(C) plays a role in tau exon 10 inclusion through the inhibitory capacity of GSK3β. MDPI 2021-05-20 /pmc/articles/PMC8161268/ /pubmed/34065232 http://dx.doi.org/10.3390/ijms22105370 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Lidón, Laia
Llaó-Hierro, Laura
Nuvolone, Mario
Aguzzi, Adriano
Ávila, Jesús
Ferrer, Isidro
del Río, José Antonio
Gavín, Rosalina
Tau Exon 10 Inclusion by PrP(C) through Downregulating GSK3β Activity
title Tau Exon 10 Inclusion by PrP(C) through Downregulating GSK3β Activity
title_full Tau Exon 10 Inclusion by PrP(C) through Downregulating GSK3β Activity
title_fullStr Tau Exon 10 Inclusion by PrP(C) through Downregulating GSK3β Activity
title_full_unstemmed Tau Exon 10 Inclusion by PrP(C) through Downregulating GSK3β Activity
title_short Tau Exon 10 Inclusion by PrP(C) through Downregulating GSK3β Activity
title_sort tau exon 10 inclusion by prp(c) through downregulating gsk3β activity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8161268/
https://www.ncbi.nlm.nih.gov/pubmed/34065232
http://dx.doi.org/10.3390/ijms22105370
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