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Title: Increased C-X-C Motif Chemokine Ligand 12 Levels in Cerebrospinal Fluid as a Candidate Biomarker in Sporadic Amyotrophic Lateral Sclerosis
Authors: Andrés-Benito, Pol
Povedano, Mònica
Domínguez, Raúl
Marco, Carla
Colomina, Maria J.
López-Pérez, Óscar
Santana, Isabel 
Baldeiras, Inês 
Martínez-Yelámos, Sergio
Zerr, Inga
Llorens, Franc
Fernández-Irigoyen, Joaquín
Santamaría, Enrique
Ferrer, Isidro
Keywords: amyotrophic lateral sclerosis; cerebrospinal fluid; proteomics; biomarkers; CXCL12; CXCR4; CXCR7; AAAS; S1006A
Issue Date: 17-Nov-2020
Publisher: MDPI
Project: Ministry of Economy and Competitiveness, Institute of Health Carlos III (ISCIII) (co-funded by European RegiSonal Development Fund, ERDF, a way to build Europe): FISPI17/000809 to IF; and FIS (ISCIII) grant PI19/00144 to FLl. 
The Proteomics Unit of Navarrabiomed is supported by grant PT17/0019/009 to JFI, of the PE I+D+I 2013-2016 funded by ISCIII and FEDER 
Spanish Ministry of Science Innovation and Universities (Ref. PID2019-110356RB-I00) 
Serial title, monograph or event: International Journal of Molecular Sciences
Volume: 21
Issue: 22
Abstract: 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.
ISSN: 1422-0067
DOI: 10.3390/ijms21228680
Rights: openAccess
Appears in Collections:I&D CNC - Artigos em Revistas Internacionais
FMUC Medicina - Artigos em Revistas Internacionais

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