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Increased C-X-C Motif Chemokine Ligand 12 Levels in Cerebrospinal Fluid as a Candidate Biomarker in Sporadic Amyotrophic Lateral Sclerosis

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Department of Pathology and Experimental Therapeutics, University of Barcelona, Feixa Llarga s/n, 08907 L’Hospitalet de Llobregat, Barcelona, Spain
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Biomedical Network Research Center on Neurodegenerative Diseases (CIBERNED), Institute Carlos III, Feixa Llarga s/n, 08907 L’Hospitalet de Llobregat, Barcelona, Spain
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Bellvitge Biomedical Research Institute (IDIBELL), 08907 L’Hospitalet de Llobregat, Barcelona, Spain
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Institute of Neurosciences, University of Barcelona, 08907 L’Hospitalet de Llobregat, Barcelona, Spain
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International Initiative for Treatment and Research Initiative to Cure ALS (TRICALS), Bellvitge University Hospital, 08907 Hospitalet de Llobregat, Spain
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Functional Unit of Amyotrophic Lateral Sclerosis (UFELA), Service of Neurology, Bellvitge University Hospital, 08907 L’Hospitalet de Llobregat, Barcelona, Spain
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Anesthesia and Critical Care Department, Bellvitge University Hospital-University of Barcelona, 08907 L’Hospitalet de Llobregat, Barcelona, Spain
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Neurology 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, Portugal
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Multiple Sclerosis Unit, Service of Neurology, Bellvitge University Hospital, 08907 L’Hospitalet de Llobregat, Barcelona, Spain
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Department of Neurology, University Medical Center Göttingen, 37075 Göttingen, Germany
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German Center for Neurodegenerative Diseases (DZNE), 37075 Göttingen, Germany
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IDISNA, Navarra Institute for Health Research, 31008 Pamplona, Spain
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Clinical Neuroproteomics Unit, Proteomics Platform, Proteored-ISCIII, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), 31008 Pamplona, Spain
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Neuropathology, Pathologic Anatomy Service, Bellvitge University Hospital, 08907 L’Hospitalet de Llobregat, Barcelona, Spain
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(22), 8680; https://doi.org/10.3390/ijms21228680
Received: 21 October 2020 / Revised: 11 November 2020 / Accepted: 16 November 2020 / Published: 17 November 2020
(This article belongs to the Section Molecular Neurobiology)
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. View Full-Text
Keywords: amyotrophic lateral sclerosis; cerebrospinal fluid; proteomics; biomarkers; CXCL12; CXCR4; CXCR7; AAAS; S1006A amyotrophic lateral sclerosis; cerebrospinal fluid; proteomics; biomarkers; CXCL12; CXCR4; CXCR7; AAAS; S1006A
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MDPI and ACS Style

Andrés-Benito, P.; Povedano, M.; Domínguez, R.; Marco, C.; Colomina, M.J.; López-Pérez, Ó.; Santana, I.; Baldeiras, I.; Martínez-Yelámos, S.; Zerr, I.; Llorens, F.; Fernández-Irigoyen, J.; Santamaría, E.; Ferrer, I. Increased C-X-C Motif Chemokine Ligand 12 Levels in Cerebrospinal Fluid as a Candidate Biomarker in Sporadic Amyotrophic Lateral Sclerosis. Int. J. Mol. Sci. 2020, 21, 8680. https://doi.org/10.3390/ijms21228680

AMA Style

Andrés-Benito P, Povedano M, Domínguez R, Marco C, Colomina MJ, López-Pérez Ó, Santana I, Baldeiras I, Martínez-Yelámos S, Zerr I, Llorens F, Fernández-Irigoyen J, Santamaría E, Ferrer I. 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. 2020; 21(22):8680. https://doi.org/10.3390/ijms21228680

Chicago/Turabian Style

Andrés-Benito, Pol, 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, and Isidro Ferrer. 2020. "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 21, no. 22: 8680. https://doi.org/10.3390/ijms21228680

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