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Dysregulated Brain Protein Phosphorylation Linked to Increased Human Tau Expression in the hTau Transgenic Mouse Model

Altered protein phosphorylation is a major pathologic modification in tauopathies and Alzheimer’s disease (AD) linked to abnormal tau fibrillar deposits in neurofibrillary tangles (NFTs) and pre-tangles and β-amyloid deposits in AD. hTau transgenic mice, which express 3R and less 4R human tau with n...

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Autores principales: Ferrer, Isidro, Andrés-Benito, Pol, Ausín, Karina, Cartas-Cejudo, Paz, Lachén-Montes, Mercedes, del Rio, José Antonio, Fernández-Irigoyen, Joaquín, Santamaría, Enrique
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9223516/
https://www.ncbi.nlm.nih.gov/pubmed/35742871
http://dx.doi.org/10.3390/ijms23126427
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author Ferrer, Isidro
Andrés-Benito, Pol
Ausín, Karina
Cartas-Cejudo, Paz
Lachén-Montes, Mercedes
del Rio, José Antonio
Fernández-Irigoyen, Joaquín
Santamaría, Enrique
author_facet Ferrer, Isidro
Andrés-Benito, Pol
Ausín, Karina
Cartas-Cejudo, Paz
Lachén-Montes, Mercedes
del Rio, José Antonio
Fernández-Irigoyen, Joaquín
Santamaría, Enrique
author_sort Ferrer, Isidro
collection PubMed
description Altered protein phosphorylation is a major pathologic modification in tauopathies and Alzheimer’s disease (AD) linked to abnormal tau fibrillar deposits in neurofibrillary tangles (NFTs) and pre-tangles and β-amyloid deposits in AD. hTau transgenic mice, which express 3R and less 4R human tau with no mutations in a murine knock-out background, show increased tau deposition in neurons but not NFTs and pre-tangles at the age of nine months. Label-free (phospho)proteomics and SWATH-MS identified 2065 proteins in hTau and wild-type (WT) mice. Only six proteins showed increased levels in hTau; no proteins were down-regulated. Increased tau phosphorylation in hTau was detected at Ser199, Ser202, Ser214, Ser396, Ser400, Thr403, Ser404, Ser413, Ser416, Ser422, Ser491, and Ser494, in addition to Thr181, Thr231, Ser396/Ser404, but not at Ser202/Thr205. In addition, 4578 phosphopeptides (corresponding to 1622 phosphoproteins) were identified in hTau and WT mice; 64 proteins were differentially phosphorylated in hTau. Sixty proteins were grouped into components of membranes, membrane signaling, synapses, vesicles, cytoskeleton, DNA/RNA/protein metabolism, ubiquitin/proteasome system, cholesterol and lipid metabolism, and cell signaling. These results showed that over-expression of human tau without pre-tangle and NFT formation preferentially triggers an imbalance in the phosphorylation profile of specific proteins involved in the cytoskeletal–membrane-signaling axis.
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spelling pubmed-92235162022-06-24 Dysregulated Brain Protein Phosphorylation Linked to Increased Human Tau Expression in the hTau Transgenic Mouse Model Ferrer, Isidro Andrés-Benito, Pol Ausín, Karina Cartas-Cejudo, Paz Lachén-Montes, Mercedes del Rio, José Antonio Fernández-Irigoyen, Joaquín Santamaría, Enrique Int J Mol Sci Article Altered protein phosphorylation is a major pathologic modification in tauopathies and Alzheimer’s disease (AD) linked to abnormal tau fibrillar deposits in neurofibrillary tangles (NFTs) and pre-tangles and β-amyloid deposits in AD. hTau transgenic mice, which express 3R and less 4R human tau with no mutations in a murine knock-out background, show increased tau deposition in neurons but not NFTs and pre-tangles at the age of nine months. Label-free (phospho)proteomics and SWATH-MS identified 2065 proteins in hTau and wild-type (WT) mice. Only six proteins showed increased levels in hTau; no proteins were down-regulated. Increased tau phosphorylation in hTau was detected at Ser199, Ser202, Ser214, Ser396, Ser400, Thr403, Ser404, Ser413, Ser416, Ser422, Ser491, and Ser494, in addition to Thr181, Thr231, Ser396/Ser404, but not at Ser202/Thr205. In addition, 4578 phosphopeptides (corresponding to 1622 phosphoproteins) were identified in hTau and WT mice; 64 proteins were differentially phosphorylated in hTau. Sixty proteins were grouped into components of membranes, membrane signaling, synapses, vesicles, cytoskeleton, DNA/RNA/protein metabolism, ubiquitin/proteasome system, cholesterol and lipid metabolism, and cell signaling. These results showed that over-expression of human tau without pre-tangle and NFT formation preferentially triggers an imbalance in the phosphorylation profile of specific proteins involved in the cytoskeletal–membrane-signaling axis. MDPI 2022-06-08 /pmc/articles/PMC9223516/ /pubmed/35742871 http://dx.doi.org/10.3390/ijms23126427 Text en © 2022 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
Ferrer, Isidro
Andrés-Benito, Pol
Ausín, Karina
Cartas-Cejudo, Paz
Lachén-Montes, Mercedes
del Rio, José Antonio
Fernández-Irigoyen, Joaquín
Santamaría, Enrique
Dysregulated Brain Protein Phosphorylation Linked to Increased Human Tau Expression in the hTau Transgenic Mouse Model
title Dysregulated Brain Protein Phosphorylation Linked to Increased Human Tau Expression in the hTau Transgenic Mouse Model
title_full Dysregulated Brain Protein Phosphorylation Linked to Increased Human Tau Expression in the hTau Transgenic Mouse Model
title_fullStr Dysregulated Brain Protein Phosphorylation Linked to Increased Human Tau Expression in the hTau Transgenic Mouse Model
title_full_unstemmed Dysregulated Brain Protein Phosphorylation Linked to Increased Human Tau Expression in the hTau Transgenic Mouse Model
title_short Dysregulated Brain Protein Phosphorylation Linked to Increased Human Tau Expression in the hTau Transgenic Mouse Model
title_sort dysregulated brain protein phosphorylation linked to increased human tau expression in the htau transgenic mouse model
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9223516/
https://www.ncbi.nlm.nih.gov/pubmed/35742871
http://dx.doi.org/10.3390/ijms23126427
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