Increased C-X-C Motif Chemokine Ligand 12 Levels in Cerebrospinal Fluid as a Candidate Biomarker in Sporadic Amyotrophic Lateral Sclerosis
Sporadic amyotrophic lateral sclerosis (sALS) is a fatal progressive neurodegenerative disease affecting upper and lower motor neurons. Biomarkers are useful to facilitate the diagnosis and/or prognosis of patients and to reveal possible mechanistic clues about the disease. This study aimed to ident...
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-11-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/21/22/8680 |
| _version_ | 1797547625111617536 |
|---|---|
| author | Pol Andrés-Benito Mònica Povedano Raúl Domínguez Carla Marco Maria J. Colomina Óscar López-Pérez Isabel Santana Inês Baldeiras Sergio Martínez-Yelámos Inga Zerr Franc Llorens Joaquín Fernández-Irigoyen Enrique Santamaría Isidro Ferrer |
| author_facet | Pol Andrés-Benito Mònica Povedano Raúl Domínguez Carla Marco Maria J. Colomina Óscar López-Pérez Isabel Santana Inês Baldeiras Sergio Martínez-Yelámos Inga Zerr Franc Llorens Joaquín Fernández-Irigoyen Enrique Santamaría Isidro Ferrer |
| author_sort | Pol Andrés-Benito |
| collection | DOAJ |
| description | Sporadic amyotrophic lateral sclerosis (sALS) is a fatal progressive neurodegenerative disease affecting upper and lower motor neurons. Biomarkers are useful to facilitate the diagnosis and/or prognosis of patients and to reveal possible mechanistic clues about the disease. This study aimed to identify and validate selected putative biomarkers in the cerebrospinal fluid (CSF) of sALS patients at early disease stages compared with age-matched controls and with other neurodegenerative diseases including Alzheimer disease (AD), spinal muscular atrophy type III (SMA), frontotemporal dementia behavioral variant (FTD), and multiple sclerosis (MS). SWATH acquisition on liquid chromatography-tandem mass spectrometry (LC–MS/MS) for protein quantitation, and ELISA for validation, were used in CSF samples of sALS cases at early stages of the disease. Analysis of mRNA and protein expression was carried out in the anterior horn of the lumbar spinal cord in post-mortem tissue of sALS cases (terminal stage) and controls using RTq-PCR, and Western blotting, and immunohistochemistry, respectively. SWATH acquisition on liquid chromatography-tandem mass spectrometry (LC–MS/MS) revealed 51 differentially expressed proteins in the CSF in sALS. Receiver operating characteristic (ROC) curves showed CXCL12 to be the most valuable candidate biomarker. We validated the values of CXCL12 in CSF with ELISA in two different cohorts. Besides sALS, increased CXCL12 levels were found in MS but were not altered in AD, SMA, and FTD. Therefore, increased CXCL12 levels in the CSF can be useful in the diagnoses of MS and sALS in the context of the clinical settings. CXCL12 immunoreactivity was localized in motor neurons in control and sALS, and in a few glial cells in sALS at the terminal stage; CXCR4 was in a subset of oligodendroglial-like cells and axonal ballooning of motor neurons in sALS; and CXCR7 in motor neurons in control and sALS, and reactive astrocytes in the pyramidal tracts in terminal sALS. CXCL12/CXCR4/CXCR7 axis in the spinal cord probably plays a complex role in inflammation, oligodendroglial and astrocyte signaling, and neuronal and axonal preservation in sALS. |
| first_indexed | 2024-03-10T14:46:43Z |
| format | Article |
| id | doaj.art-5882d215276a46838769ce7ae1a9c986 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T14:46:43Z |
| publishDate | 2020-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-5882d215276a46838769ce7ae1a9c9862023-11-20T21:18:32ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-11-012122868010.3390/ijms21228680Increased C-X-C Motif Chemokine Ligand 12 Levels in Cerebrospinal Fluid as a Candidate Biomarker in Sporadic Amyotrophic Lateral SclerosisPol Andrés-Benito0Mònica Povedano1Raúl Domínguez2Carla Marco3Maria J. Colomina4Óscar López-Pérez5Isabel Santana6Inês Baldeiras7Sergio Martínez-Yelámos8Inga Zerr9Franc Llorens10Joaquín Fernández-Irigoyen11Enrique Santamaría12Isidro Ferrer13Department of Pathology and Experimental Therapeutics, University of Barcelona, Feixa Llarga s/n, 08907 L’Hospitalet de Llobregat, Barcelona, SpainInternational Initiative for Treatment and Research Initiative to Cure ALS (TRICALS), Bellvitge University Hospital, 08907 Hospitalet de Llobregat, SpainInternational Initiative for Treatment and Research Initiative to Cure ALS (TRICALS), Bellvitge University Hospital, 08907 Hospitalet de Llobregat, SpainInternational Initiative for Treatment and Research Initiative to Cure ALS (TRICALS), Bellvitge University Hospital, 08907 Hospitalet de Llobregat, SpainAnesthesia and Critical Care Department, Bellvitge University Hospital-University of Barcelona, 08907 L’Hospitalet de Llobregat, Barcelona, SpainBiomedical Network Research Center on Neurodegenerative Diseases (CIBERNED), Institute Carlos III, Feixa Llarga s/n, 08907 L’Hospitalet de Llobregat, Barcelona, SpainNeurology Department, CHUC—Centro Hospitalar e Universitário de Coimbra, CNC—Center for Neuroscience and Cell Biology; and Faculty of Medicine, University of Coimbra, 3000-456 Coimbra, PortugalNeurology Department, CHUC—Centro Hospitalar e Universitário de Coimbra, CNC—Center for Neuroscience and Cell Biology; and Faculty of Medicine, University of Coimbra, 3000-456 Coimbra, PortugalMultiple Sclerosis Unit, Service of Neurology, Bellvitge University Hospital, 08907 L’Hospitalet de Llobregat, Barcelona, SpainDepartment of Neurology, University Medical Center Göttingen, 37075 Göttingen, GermanyDepartment of Pathology and Experimental Therapeutics, University of Barcelona, Feixa Llarga s/n, 08907 L’Hospitalet de Llobregat, Barcelona, SpainIDISNA, Navarra Institute for Health Research, 31008 Pamplona, SpainIDISNA, Navarra Institute for Health Research, 31008 Pamplona, SpainDepartment of Pathology and Experimental Therapeutics, University of Barcelona, Feixa Llarga s/n, 08907 L’Hospitalet de Llobregat, Barcelona, SpainSporadic amyotrophic lateral sclerosis (sALS) is a fatal progressive neurodegenerative disease affecting upper and lower motor neurons. Biomarkers are useful to facilitate the diagnosis and/or prognosis of patients and to reveal possible mechanistic clues about the disease. This study aimed to identify and validate selected putative biomarkers in the cerebrospinal fluid (CSF) of sALS patients at early disease stages compared with age-matched controls and with other neurodegenerative diseases including Alzheimer disease (AD), spinal muscular atrophy type III (SMA), frontotemporal dementia behavioral variant (FTD), and multiple sclerosis (MS). SWATH acquisition on liquid chromatography-tandem mass spectrometry (LC–MS/MS) for protein quantitation, and ELISA for validation, were used in CSF samples of sALS cases at early stages of the disease. Analysis of mRNA and protein expression was carried out in the anterior horn of the lumbar spinal cord in post-mortem tissue of sALS cases (terminal stage) and controls using RTq-PCR, and Western blotting, and immunohistochemistry, respectively. SWATH acquisition on liquid chromatography-tandem mass spectrometry (LC–MS/MS) revealed 51 differentially expressed proteins in the CSF in sALS. Receiver operating characteristic (ROC) curves showed CXCL12 to be the most valuable candidate biomarker. We validated the values of CXCL12 in CSF with ELISA in two different cohorts. Besides sALS, increased CXCL12 levels were found in MS but were not altered in AD, SMA, and FTD. Therefore, increased CXCL12 levels in the CSF can be useful in the diagnoses of MS and sALS in the context of the clinical settings. CXCL12 immunoreactivity was localized in motor neurons in control and sALS, and in a few glial cells in sALS at the terminal stage; CXCR4 was in a subset of oligodendroglial-like cells and axonal ballooning of motor neurons in sALS; and CXCR7 in motor neurons in control and sALS, and reactive astrocytes in the pyramidal tracts in terminal sALS. CXCL12/CXCR4/CXCR7 axis in the spinal cord probably plays a complex role in inflammation, oligodendroglial and astrocyte signaling, and neuronal and axonal preservation in sALS.https://www.mdpi.com/1422-0067/21/22/8680amyotrophic lateral sclerosiscerebrospinal fluidproteomicsbiomarkersCXCL12CXCR4 |
| spellingShingle | Pol Andrés-Benito Mònica Povedano Raúl Domínguez Carla Marco Maria J. Colomina Óscar López-Pérez Isabel Santana Inês Baldeiras Sergio Martínez-Yelámos Inga Zerr Franc Llorens Joaquín Fernández-Irigoyen Enrique Santamaría Isidro Ferrer Increased C-X-C Motif Chemokine Ligand 12 Levels in Cerebrospinal Fluid as a Candidate Biomarker in Sporadic Amyotrophic Lateral Sclerosis International Journal of Molecular Sciences amyotrophic lateral sclerosis cerebrospinal fluid proteomics biomarkers CXCL12 CXCR4 |
| title | Increased C-X-C Motif Chemokine Ligand 12 Levels in Cerebrospinal Fluid as a Candidate Biomarker in Sporadic Amyotrophic Lateral Sclerosis |
| title_full | Increased C-X-C Motif Chemokine Ligand 12 Levels in Cerebrospinal Fluid as a Candidate Biomarker in Sporadic Amyotrophic Lateral Sclerosis |
| title_fullStr | Increased C-X-C Motif Chemokine Ligand 12 Levels in Cerebrospinal Fluid as a Candidate Biomarker in Sporadic Amyotrophic Lateral Sclerosis |
| title_full_unstemmed | Increased C-X-C Motif Chemokine Ligand 12 Levels in Cerebrospinal Fluid as a Candidate Biomarker in Sporadic Amyotrophic Lateral Sclerosis |
| title_short | Increased C-X-C Motif Chemokine Ligand 12 Levels in Cerebrospinal Fluid as a Candidate Biomarker in Sporadic Amyotrophic Lateral Sclerosis |
| title_sort | increased c x c motif chemokine ligand 12 levels in cerebrospinal fluid as a candidate biomarker in sporadic amyotrophic lateral sclerosis |
| topic | amyotrophic lateral sclerosis cerebrospinal fluid proteomics biomarkers CXCL12 CXCR4 |
| url | https://www.mdpi.com/1422-0067/21/22/8680 |
| work_keys_str_mv | AT polandresbenito increasedcxcmotifchemokineligand12levelsincerebrospinalfluidasacandidatebiomarkerinsporadicamyotrophiclateralsclerosis AT monicapovedano increasedcxcmotifchemokineligand12levelsincerebrospinalfluidasacandidatebiomarkerinsporadicamyotrophiclateralsclerosis AT rauldominguez increasedcxcmotifchemokineligand12levelsincerebrospinalfluidasacandidatebiomarkerinsporadicamyotrophiclateralsclerosis AT carlamarco increasedcxcmotifchemokineligand12levelsincerebrospinalfluidasacandidatebiomarkerinsporadicamyotrophiclateralsclerosis AT mariajcolomina increasedcxcmotifchemokineligand12levelsincerebrospinalfluidasacandidatebiomarkerinsporadicamyotrophiclateralsclerosis AT oscarlopezperez increasedcxcmotifchemokineligand12levelsincerebrospinalfluidasacandidatebiomarkerinsporadicamyotrophiclateralsclerosis AT isabelsantana increasedcxcmotifchemokineligand12levelsincerebrospinalfluidasacandidatebiomarkerinsporadicamyotrophiclateralsclerosis AT inesbaldeiras increasedcxcmotifchemokineligand12levelsincerebrospinalfluidasacandidatebiomarkerinsporadicamyotrophiclateralsclerosis AT sergiomartinezyelamos increasedcxcmotifchemokineligand12levelsincerebrospinalfluidasacandidatebiomarkerinsporadicamyotrophiclateralsclerosis AT ingazerr increasedcxcmotifchemokineligand12levelsincerebrospinalfluidasacandidatebiomarkerinsporadicamyotrophiclateralsclerosis AT francllorens increasedcxcmotifchemokineligand12levelsincerebrospinalfluidasacandidatebiomarkerinsporadicamyotrophiclateralsclerosis AT joaquinfernandezirigoyen increasedcxcmotifchemokineligand12levelsincerebrospinalfluidasacandidatebiomarkerinsporadicamyotrophiclateralsclerosis AT enriquesantamaria increasedcxcmotifchemokineligand12levelsincerebrospinalfluidasacandidatebiomarkerinsporadicamyotrophiclateralsclerosis AT isidroferrer increasedcxcmotifchemokineligand12levelsincerebrospinalfluidasacandidatebiomarkerinsporadicamyotrophiclateralsclerosis |