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Decreased Levels of Foldase and Chaperone Proteins Are Associated with an Early-Onset Amyotrophic Lateral Sclerosis
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive upper and lower motor neuron degeneration. One of the peculiar clinical characteristics of ALS is the wide distribution in age of onset, which is probably caused by different combinations of intri...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5382314/ https://www.ncbi.nlm.nih.gov/pubmed/28428745 http://dx.doi.org/10.3389/fnmol.2017.00099 |
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author | Filareti, Melania Luotti, Silvia Pasetto, Laura Pignataro, Mauro Paolella, Katia Messina, Paolo Pupillo, Elisabetta Filosto, Massimiliano Lunetta, Christian Mandrioli, Jessica Fuda, Giuseppe Calvo, Andrea Chiò, Adriano Corbo, Massimo Bendotti, Caterina Beghi, Ettore Bonetto, Valentina |
author_facet | Filareti, Melania Luotti, Silvia Pasetto, Laura Pignataro, Mauro Paolella, Katia Messina, Paolo Pupillo, Elisabetta Filosto, Massimiliano Lunetta, Christian Mandrioli, Jessica Fuda, Giuseppe Calvo, Andrea Chiò, Adriano Corbo, Massimo Bendotti, Caterina Beghi, Ettore Bonetto, Valentina |
author_sort | Filareti, Melania |
collection | PubMed |
description | Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive upper and lower motor neuron degeneration. One of the peculiar clinical characteristics of ALS is the wide distribution in age of onset, which is probably caused by different combinations of intrinsic and exogenous factors. We investigated whether these modifying factors are converging into common pathogenic pathways leading either to an early or a late disease onset. This would imply the identification of phenotypic biomarkers, that can distinguish the two populations of ALS patients, and of relevant pathways to consider in a therapeutic intervention. Toward this aim a differential proteomic analysis was performed in peripheral blood mononuclear cells (PBMC) from a group of 16 ALS patients with an age of onset ≤55 years and a group of 16 ALS patients with an age of onset ≥75 years, and matched healthy controls. We identified 43 differentially expressed proteins in the two groups of patients. Gene ontology analysis revealed that there was a significant enrichment in annotations associated with protein folding and response to stress. We next validated a selected number of proteins belonging to this functional group in 85 patients and 83 age- and sex-matched healthy controls using immunoassays. The results of the validation study confirmed that there was a decreased level of peptidyl-prolyl cis-trans isomerase A (also known as cyclophilin A), heat shock protein HSP 90-alpha, 78 kDa glucose-regulated protein (also known as BiP) and protein deglycase DJ-1 in PBMC of ALS patients with an early onset. Similar results were obtained in PBMC and spinal cord from two SOD1(G93A) mouse models with an early and late disease onset. This study suggests that a different ability to upregulate proteins involved in proteostasis, such as foldase and chaperone proteins, may be at the basis of a different susceptibility to ALS, putting forward the development of therapeutic approaches aiming at boosting the protein quality control system. |
format | Online Article Text |
id | pubmed-5382314 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-53823142017-04-20 Decreased Levels of Foldase and Chaperone Proteins Are Associated with an Early-Onset Amyotrophic Lateral Sclerosis Filareti, Melania Luotti, Silvia Pasetto, Laura Pignataro, Mauro Paolella, Katia Messina, Paolo Pupillo, Elisabetta Filosto, Massimiliano Lunetta, Christian Mandrioli, Jessica Fuda, Giuseppe Calvo, Andrea Chiò, Adriano Corbo, Massimo Bendotti, Caterina Beghi, Ettore Bonetto, Valentina Front Mol Neurosci Neuroscience Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive upper and lower motor neuron degeneration. One of the peculiar clinical characteristics of ALS is the wide distribution in age of onset, which is probably caused by different combinations of intrinsic and exogenous factors. We investigated whether these modifying factors are converging into common pathogenic pathways leading either to an early or a late disease onset. This would imply the identification of phenotypic biomarkers, that can distinguish the two populations of ALS patients, and of relevant pathways to consider in a therapeutic intervention. Toward this aim a differential proteomic analysis was performed in peripheral blood mononuclear cells (PBMC) from a group of 16 ALS patients with an age of onset ≤55 years and a group of 16 ALS patients with an age of onset ≥75 years, and matched healthy controls. We identified 43 differentially expressed proteins in the two groups of patients. Gene ontology analysis revealed that there was a significant enrichment in annotations associated with protein folding and response to stress. We next validated a selected number of proteins belonging to this functional group in 85 patients and 83 age- and sex-matched healthy controls using immunoassays. The results of the validation study confirmed that there was a decreased level of peptidyl-prolyl cis-trans isomerase A (also known as cyclophilin A), heat shock protein HSP 90-alpha, 78 kDa glucose-regulated protein (also known as BiP) and protein deglycase DJ-1 in PBMC of ALS patients with an early onset. Similar results were obtained in PBMC and spinal cord from two SOD1(G93A) mouse models with an early and late disease onset. This study suggests that a different ability to upregulate proteins involved in proteostasis, such as foldase and chaperone proteins, may be at the basis of a different susceptibility to ALS, putting forward the development of therapeutic approaches aiming at boosting the protein quality control system. Frontiers Media S.A. 2017-04-06 /pmc/articles/PMC5382314/ /pubmed/28428745 http://dx.doi.org/10.3389/fnmol.2017.00099 Text en Copyright © 2017 Filareti, Luotti, Pasetto, Pignataro, Paolella, Messina, Pupillo, Filosto, Lunetta, Mandrioli, Fuda, Calvo, Chiò, Corbo, Bendotti, Beghi and Bonetto. http://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) or licensor 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 | Neuroscience Filareti, Melania Luotti, Silvia Pasetto, Laura Pignataro, Mauro Paolella, Katia Messina, Paolo Pupillo, Elisabetta Filosto, Massimiliano Lunetta, Christian Mandrioli, Jessica Fuda, Giuseppe Calvo, Andrea Chiò, Adriano Corbo, Massimo Bendotti, Caterina Beghi, Ettore Bonetto, Valentina Decreased Levels of Foldase and Chaperone Proteins Are Associated with an Early-Onset Amyotrophic Lateral Sclerosis |
title | Decreased Levels of Foldase and Chaperone Proteins Are Associated with an Early-Onset Amyotrophic Lateral Sclerosis |
title_full | Decreased Levels of Foldase and Chaperone Proteins Are Associated with an Early-Onset Amyotrophic Lateral Sclerosis |
title_fullStr | Decreased Levels of Foldase and Chaperone Proteins Are Associated with an Early-Onset Amyotrophic Lateral Sclerosis |
title_full_unstemmed | Decreased Levels of Foldase and Chaperone Proteins Are Associated with an Early-Onset Amyotrophic Lateral Sclerosis |
title_short | Decreased Levels of Foldase and Chaperone Proteins Are Associated with an Early-Onset Amyotrophic Lateral Sclerosis |
title_sort | decreased levels of foldase and chaperone proteins are associated with an early-onset amyotrophic lateral sclerosis |
topic | Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5382314/ https://www.ncbi.nlm.nih.gov/pubmed/28428745 http://dx.doi.org/10.3389/fnmol.2017.00099 |
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