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Comprehensive Characterization of CK1δ-Mediated Tau Phosphorylation in Alzheimer’s Disease

A main pathological event in Alzheimer’s disease is the generation of neurofibrillary tangles originating from hyperphosphorylated and subsequently aggregated tau proteins. Previous reports demonstrated the critical involvement of members of the protein kinase family CK1 in the pathogenesis of Alzhe...

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Autores principales: Roth, Aileen, Sander, Annabelle, Oswald, Marleen Silke, Gärtner, Fabian, Knippschild, Uwe, Bischof, Joachim
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9531328/
https://www.ncbi.nlm.nih.gov/pubmed/36203870
http://dx.doi.org/10.3389/fmolb.2022.872171
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author Roth, Aileen
Sander, Annabelle
Oswald, Marleen Silke
Gärtner, Fabian
Knippschild, Uwe
Bischof, Joachim
author_facet Roth, Aileen
Sander, Annabelle
Oswald, Marleen Silke
Gärtner, Fabian
Knippschild, Uwe
Bischof, Joachim
author_sort Roth, Aileen
collection PubMed
description A main pathological event in Alzheimer’s disease is the generation of neurofibrillary tangles originating from hyperphosphorylated and subsequently aggregated tau proteins. Previous reports demonstrated the critical involvement of members of the protein kinase family CK1 in the pathogenesis of Alzheimer’s disease by hyperphosphorylation of tau. However, precise mechanisms and effects of CK1-mediated tau phosphorylation are still not fully understood. In this study, we analyzed recombinant tau441 phosphorylated by CK1δ in vitro via mass spectrometry and identified ten potential phosphorylation sites, five of them are associated to Alzheimer’s disease. To confirm these results, in vitro kinase assays and two-dimensional phosphopeptide analyses were performed with tau441 phosphomutants confirming Alzheimer’s disease-associated residues Ser68/Thr71 and Ser289 as CK1δ-specific phosphorylation sites. Treatment of differentiated human neural progenitor cells with PF-670462 and Western blot analysis identified Ser214 as CK1δ-targeted phosphorylation site. The use of an in vitro tau aggregation assay demonstrated a possible role of CK1δ in tau aggregation. Results obtained in this study highlight the potential of CK1δ to be a promising target in the treatment of Alzheimer’s disease.
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spelling pubmed-95313282022-10-05 Comprehensive Characterization of CK1δ-Mediated Tau Phosphorylation in Alzheimer’s Disease Roth, Aileen Sander, Annabelle Oswald, Marleen Silke Gärtner, Fabian Knippschild, Uwe Bischof, Joachim Front Mol Biosci Molecular Biosciences A main pathological event in Alzheimer’s disease is the generation of neurofibrillary tangles originating from hyperphosphorylated and subsequently aggregated tau proteins. Previous reports demonstrated the critical involvement of members of the protein kinase family CK1 in the pathogenesis of Alzheimer’s disease by hyperphosphorylation of tau. However, precise mechanisms and effects of CK1-mediated tau phosphorylation are still not fully understood. In this study, we analyzed recombinant tau441 phosphorylated by CK1δ in vitro via mass spectrometry and identified ten potential phosphorylation sites, five of them are associated to Alzheimer’s disease. To confirm these results, in vitro kinase assays and two-dimensional phosphopeptide analyses were performed with tau441 phosphomutants confirming Alzheimer’s disease-associated residues Ser68/Thr71 and Ser289 as CK1δ-specific phosphorylation sites. Treatment of differentiated human neural progenitor cells with PF-670462 and Western blot analysis identified Ser214 as CK1δ-targeted phosphorylation site. The use of an in vitro tau aggregation assay demonstrated a possible role of CK1δ in tau aggregation. Results obtained in this study highlight the potential of CK1δ to be a promising target in the treatment of Alzheimer’s disease. Frontiers Media S.A. 2022-06-27 /pmc/articles/PMC9531328/ /pubmed/36203870 http://dx.doi.org/10.3389/fmolb.2022.872171 Text en Copyright © 2022 Roth, Sander, Oswald, Gärtner, Knippschild and Bischof. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Molecular Biosciences
Roth, Aileen
Sander, Annabelle
Oswald, Marleen Silke
Gärtner, Fabian
Knippschild, Uwe
Bischof, Joachim
Comprehensive Characterization of CK1δ-Mediated Tau Phosphorylation in Alzheimer’s Disease
title Comprehensive Characterization of CK1δ-Mediated Tau Phosphorylation in Alzheimer’s Disease
title_full Comprehensive Characterization of CK1δ-Mediated Tau Phosphorylation in Alzheimer’s Disease
title_fullStr Comprehensive Characterization of CK1δ-Mediated Tau Phosphorylation in Alzheimer’s Disease
title_full_unstemmed Comprehensive Characterization of CK1δ-Mediated Tau Phosphorylation in Alzheimer’s Disease
title_short Comprehensive Characterization of CK1δ-Mediated Tau Phosphorylation in Alzheimer’s Disease
title_sort comprehensive characterization of ck1δ-mediated tau phosphorylation in alzheimer’s disease
topic Molecular Biosciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9531328/
https://www.ncbi.nlm.nih.gov/pubmed/36203870
http://dx.doi.org/10.3389/fmolb.2022.872171
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