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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...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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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. |
format | Online Article Text |
id | pubmed-9531328 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
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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