title: Label-Free LC-MS/MS Proteomic Analysis of Cerebrospinal Fluid Identifies Protein/Pathway Alterations and Candidate Biomarkers for Amyotrophic Lateral Sclerosis.
abstract: Analysis of the cerebrospinal fluid (CSF) proteome has proven valuable to the study of neurodegenerative disorders. To identify new protein/pathway alterations and candidate biomarkers for amyotrophic lateral sclerosis (ALS), we performed comparative proteomic profiling of CSF from sporadic ALS (sALS), healthy control (HC), and other neurological disease (OND) subjects using label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS). A total of 1712 CSF proteins were detected and relatively quantified by spectral counting. Levels of several proteins with diverse biological functions were significantly altered in sALS samples. Enrichment analysis was used to link these alterations to biological pathways, which were predominantly related to inflammation, neuronal activity, and extracellular matrix regulation. We then used our CSF proteomic profiles to create a support vector machines classifier capable of discriminating training set ALS from non-ALS (HC and OND) samples. Four classifier proteins, WD repeat-containing protein 63, amyloid-like protein 1, SPARC-like protein 1, and cell adhesion molecule 3, were identified by feature selection and externally validated. The resultant classifier distinguished ALS from non-ALS samples with 83% sensitivity and 100% specificity in an independent test set. Collectively, our results illustrate the utility of CSF proteomic profiling for identifying ALS protein/pathway alterations and candidate disease biomarkers.
authors.affiliation: Department of Neurobiology, University of Pittsburgh , E1448 Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, Pennsylvania 15261, United States.|Departments of Neurology and Neurobiology, Barrow Neurological Institute , NRC427, 350 West Thomas Road, Phoenix, Arizona 85013, United States.
authors.forename: Mahlon A
authors.initials: MA
authors.lastname: Collins
authors.affiliation: Departments of Neurology and Neurobiology, Barrow Neurological Institute , NRC427, 350 West Thomas Road, Phoenix, Arizona 85013, United States.
authors.forename: Jiyan
authors.initials: J
authors.lastname: An
authors.affiliation: Women's Health Integrated Research Center , 3289 Woodburn Road, Annandale, Virginia 22003, United States.
authors.forename: Brian L
authors.initials: BL
authors.lastname: Hood
authors.affiliation: Women's Health Integrated Research Center , 3289 Woodburn Road, Annandale, Virginia 22003, United States.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Conrads
authors.affiliation: Departments of Neurology and Neurobiology, Barrow Neurological Institute , NRC427, 350 West Thomas Road, Phoenix, Arizona 85013, United States.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Bowser
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000134:cerebrospinal fluid / Q000235:genetics / Q000302:isolation & purification; D000328:Adult; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000134:cerebrospinal fluid / Q000235:genetics / Q000302:isolation & purification; D000690:Amyotrophic Lateral Sclerosis / Q000134:cerebrospinal fluid / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D015415:Biomarkers / Q000134:cerebrospinal fluid; D002135:Calcium-Binding Proteins / Q000134:cerebrospinal fluid / Q000235:genetics / Q000302:isolation & purification; D016022:Case-Control Studies; D015815:Cell Adhesion Molecules / Q000134:cerebrospinal fluid / Q000235:genetics / Q000302:isolation & purification; D002556:Cerebrospinal Fluid Proteins / Q000134:cerebrospinal fluid / Q000235:genetics / Q000302:isolation & purification*; D002853:Chromatography, Liquid / Q000379:methods; D003937:Diagnosis, Differential; D005109:Extracellular Matrix / Q000737:chemistry; D016326:Extracellular Matrix Proteins / Q000134:cerebrospinal fluid / Q000235:genetics / Q000302:isolation & purification; D006801:Humans; D007136:Immunoglobulins / Q000134:cerebrospinal fluid / Q000235:genetics / Q000302:isolation & purification; D007249:Inflammation; D008875:Middle Aged; D016472:Motor Neuron Disease / Q000134:cerebrospinal fluid / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D020543:Proteome / Q000235:genetics / Q000302:isolation & purification* / Q000378:metabolism; D040901:Proteomics / Q000379:methods; D012680:Sensitivity and Specificity; D060388:Support Vector Machine; D013569:Synapses / Q000235:genetics / Q000378:metabolism; D009435:Synaptic Transmission; D053719:Tandem Mass Spectrometry / Q000379:methods
chemical_list: C489697:APLP1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D016564:Amyloid beta-Protein Precursor; D015415:Biomarkers; C498599:CADM3 protein, human; D002135:Calcium-Binding Proteins; D015815:Cell Adhesion Molecules; D002556:Cerebrospinal Fluid Proteins; D016326:Extracellular Matrix Proteins; D007136:Immunoglobulins; D020543:Proteome; C503126:SPARCL1 protein, human
keywords: LC−MS/MS; amyotrophic lateral sclerosis; biomarker; cerebrospinal fluid; extracellular matrix; liquid chromatography-tandem mass spectrometry; mass spectrometry; proteomics