Dysregulated protein phosphorylation: a determining condition in the continuum of brain aging and Alzheimer's disease
Tau hyperphosphorylation is the first step of neurofibrillary tangle (NFT) formation. In the present study, samples of the entorhinal cortex (EC) and frontal cortex area 8 (FC) of cases with NFT pathology classified as stages I–II, III–IV, and V–VI without comorbidities, and of middle-aged (MA) indi...
| Autores: | , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2021 |
| País: | España |
| Institución: | Universidad Pública de Navarra |
| Repositorio: | Academica-e. Repositorio Institucional de la Universidad Pública de Navarra |
| OAI Identifier: | oai:academica-e.unavarra.es:2454/41672 |
| Acceso en línea: | https://hdl.handle.net/2454/41672 |
| Access Level: | acceso abierto |
| Palabra clave: | (Phospho)Proteomics Alzheimer&apos s disease Brain aging Cytoskeleton Kinases Membranes Protein phosphorylation Synapses Tau |
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España |
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| dc.title.none.fl_str_mv |
Dysregulated protein phosphorylation: a determining condition in the continuum of brain aging and Alzheimer's disease |
| title |
Dysregulated protein phosphorylation: a determining condition in the continuum of brain aging and Alzheimer's disease |
| spellingShingle |
Dysregulated protein phosphorylation: a determining condition in the continuum of brain aging and Alzheimer's disease Ferrer, Isidro (Phospho)Proteomics Alzheimer&apos s disease Brain aging Cytoskeleton Kinases Membranes Protein phosphorylation Synapses Tau |
| title_short |
Dysregulated protein phosphorylation: a determining condition in the continuum of brain aging and Alzheimer's disease |
| title_full |
Dysregulated protein phosphorylation: a determining condition in the continuum of brain aging and Alzheimer's disease |
| title_fullStr |
Dysregulated protein phosphorylation: a determining condition in the continuum of brain aging and Alzheimer's disease |
| title_full_unstemmed |
Dysregulated protein phosphorylation: a determining condition in the continuum of brain aging and Alzheimer's disease |
| title_sort |
Dysregulated protein phosphorylation: a determining condition in the continuum of brain aging and Alzheimer's disease |
| dc.creator.none.fl_str_mv |
Ferrer, Isidro Andrés Benito, Pol Ausín, Karina Pamplona, Reinald Río, José Antonio del Fernández Irigoyen, Joaquín Santamaría Martínez, Enrique |
| author |
Ferrer, Isidro |
| author_facet |
Ferrer, Isidro Andrés Benito, Pol Ausín, Karina Pamplona, Reinald Río, José Antonio del Fernández Irigoyen, Joaquín Santamaría Martínez, Enrique |
| author_role |
author |
| author2 |
Andrés Benito, Pol Ausín, Karina Pamplona, Reinald Río, José Antonio del Fernández Irigoyen, Joaquín Santamaría Martínez, Enrique |
| author2_role |
author author author author author author |
| dc.contributor.none.fl_str_mv |
Ciencias de la Salud Osasun Zientziak Gobierno de Navarra / Nafarroako Gobernua |
| dc.subject.none.fl_str_mv |
(Phospho)Proteomics Alzheimer&apos s disease Brain aging Cytoskeleton Kinases Membranes Protein phosphorylation Synapses Tau |
| topic |
(Phospho)Proteomics Alzheimer&apos s disease Brain aging Cytoskeleton Kinases Membranes Protein phosphorylation Synapses Tau |
| description |
Tau hyperphosphorylation is the first step of neurofibrillary tangle (NFT) formation. In the present study, samples of the entorhinal cortex (EC) and frontal cortex area 8 (FC) of cases with NFT pathology classified as stages I–II, III–IV, and V–VI without comorbidities, and of middle-aged (MA) individuals with no NFT pathology, were analyzed by conventional label-free and SWATH-MS (sequential window acquisition of all theoretical fragment ion spectra mass spectrometry) to assess the (phospho)proteomes. The total number of identified dysregulated phosphoproteins was 214 in the EC, 65 of which were dysregulated at the first stages (I–II) of NFT pathology; 167 phosphoproteins were dysregulated in the FC, 81 of them at stages I–II of NFT pathology. A large percentage of dysregulated phosphoproteins were identified in the two regions and at different stages of NFT progression. The main group of dysregulated phosphoproteins was made up of components of the membranes, cytoskeleton, synapses, proteins linked to membrane transport and ion channels, and kinases. The present results show abnormal phosphorylation of proteins at the first stages of NFT pathology in the elderly (in individuals clinically considered representative of normal aging) and sporadic Alzheimer's disease (sAD). Dysregulated protein phosphorylation in the FC precedes the formation of NFTs and SPs. The most active period of dysregulated phosphorylation is at stages III–IV when a subpopulation of individuals might be clinically categorized as suffering from mild cognitive impairment which is a preceding determinant stage in the progression to dementia. Altered phosphorylation of selected proteins, carried out by activation of several kinases, may alter membrane and cytoskeletal functions, among them synaptic transmission and membrane/cytoskeleton signaling. Besides their implications in sAD, the present observations suggest a molecular substrate for 'benign' cognitive deterioration in 'normal' brain aging. |
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2021 |
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2021 |
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info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion |
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article |
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publishedVersion |
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https://hdl.handle.net/2454/41672 |
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https://hdl.handle.net/2454/41672 |
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Inglés |
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Inglés |
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info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-110356RB-I00 |
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© 2021 The Authors. Creative Commons Attribution-NonCommercial-NoDerivs License https://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess |
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© 2021 The Authors. Creative Commons Attribution-NonCommercial-NoDerivs License https://creativecommons.org/licenses/by-nc-nd/4.0/ |
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openAccess |
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application/pdf |
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Wiley |
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Wiley |
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reponame:Academica-e. Repositorio Institucional de la Universidad Pública de Navarra instname:Universidad Pública de Navarra |
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Universidad Pública de Navarra |
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Academica-e. Repositorio Institucional de la Universidad Pública de Navarra |
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Academica-e. Repositorio Institucional de la Universidad Pública de Navarra |
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1869412603218886656 |
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Dysregulated protein phosphorylation: a determining condition in the continuum of brain aging and Alzheimer's diseaseFerrer, IsidroAndrés Benito, PolAusín, KarinaPamplona, ReinaldRío, José Antonio delFernández Irigoyen, JoaquínSantamaría Martínez, Enrique(Phospho)ProteomicsAlzheimer&aposs diseaseBrain agingCytoskeletonKinasesMembranesProtein phosphorylationSynapsesTauTau hyperphosphorylation is the first step of neurofibrillary tangle (NFT) formation. In the present study, samples of the entorhinal cortex (EC) and frontal cortex area 8 (FC) of cases with NFT pathology classified as stages I–II, III–IV, and V–VI without comorbidities, and of middle-aged (MA) individuals with no NFT pathology, were analyzed by conventional label-free and SWATH-MS (sequential window acquisition of all theoretical fragment ion spectra mass spectrometry) to assess the (phospho)proteomes. The total number of identified dysregulated phosphoproteins was 214 in the EC, 65 of which were dysregulated at the first stages (I–II) of NFT pathology; 167 phosphoproteins were dysregulated in the FC, 81 of them at stages I–II of NFT pathology. A large percentage of dysregulated phosphoproteins were identified in the two regions and at different stages of NFT progression. The main group of dysregulated phosphoproteins was made up of components of the membranes, cytoskeleton, synapses, proteins linked to membrane transport and ion channels, and kinases. The present results show abnormal phosphorylation of proteins at the first stages of NFT pathology in the elderly (in individuals clinically considered representative of normal aging) and sporadic Alzheimer's disease (sAD). Dysregulated protein phosphorylation in the FC precedes the formation of NFTs and SPs. The most active period of dysregulated phosphorylation is at stages III–IV when a subpopulation of individuals might be clinically categorized as suffering from mild cognitive impairment which is a preceding determinant stage in the progression to dementia. Altered phosphorylation of selected proteins, carried out by activation of several kinases, may alter membrane and cytoskeletal functions, among them synaptic transmission and membrane/cytoskeleton signaling. Besides their implications in sAD, the present observations suggest a molecular substrate for 'benign' cognitive deterioration in 'normal' brain aging.The Proteomics Platform of Navarrabiomed is a member of Proteored (PRB3‐ISCIII). The project leading to these results has received funding from 'La Caixa' Banking Foundation under the project HR18‐00452 to IF; it was also supported by the Ministry of Economy and Competitiveness, Institute of Health Carlos III (ISCIII) (co‐funded by European Regional Development Fund, ERDF, a way to build Europe): FISPI17/000809 to IF; co‐financed by ERDF under the program Interreg Poctefa: RedPrion 148/16 to IF; and the Intra‐CIBERNED 2019 collaborative project to IF and JADR. We thank CERCA Programme/Generalitat de Catalunya for institutional support. We also thank CIBERNED (Instituto de Salud Carlos III: ISCIII), Ministry of Economy and Competitiveness for institutional backing. The Proteomics Platform of Navarrabiomed is supported by grant PT17/0019/009 to JFI, of the PE I+D+I 2013‐2016 funded by ISCIII and FEDER. Part of this work was funded by a grant from the Spanish Ministry of Science Innovation and Universities (Ref. PID2019‐110356RB‐I00) to JFI and ES, and the Department of Economic and Business Development from the Government of Navarra (Ref. 0011‐1411‐2020‐000028) to ESWileyCiencias de la SaludOsasun ZientziakGobierno de Navarra / Nafarroako Gobernua2021info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2454/41672reponame:Academica-e. Repositorio Institucional de la Universidad Pública de Navarrainstname:Universidad Pública de NavarraInglésinfo:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-110356RB-I00© 2021 The Authors. Creative Commons Attribution-NonCommercial-NoDerivs Licensehttps://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:academica-e.unavarra.es:2454/416722026-06-17T12:41:47Z |
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15,811543 |