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.
Keywords:
LC−MS/MS; amyotrophic lateral sclerosis; biomarker; cerebrospinal fluid; extracellular matrix; liquid chromatography-tandem mass spectrometry; mass spectrometry; proteomics.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / cerebrospinal fluid
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / isolation & purification
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Adult
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Alzheimer Disease / cerebrospinal fluid
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Alzheimer Disease / diagnosis*
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Alzheimer Disease / genetics
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Alzheimer Disease / pathology
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Amyloid beta-Protein Precursor / cerebrospinal fluid
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Amyloid beta-Protein Precursor / genetics
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Amyloid beta-Protein Precursor / isolation & purification
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Amyotrophic Lateral Sclerosis / cerebrospinal fluid
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Amyotrophic Lateral Sclerosis / diagnosis*
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Amyotrophic Lateral Sclerosis / genetics
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Amyotrophic Lateral Sclerosis / pathology
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Biomarkers / cerebrospinal fluid
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Calcium-Binding Proteins / cerebrospinal fluid
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Calcium-Binding Proteins / genetics
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Calcium-Binding Proteins / isolation & purification
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Case-Control Studies
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Cell Adhesion Molecules / cerebrospinal fluid
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Cell Adhesion Molecules / genetics
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Cell Adhesion Molecules / isolation & purification
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Cerebrospinal Fluid Proteins / cerebrospinal fluid
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Cerebrospinal Fluid Proteins / genetics
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Cerebrospinal Fluid Proteins / isolation & purification*
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Chromatography, Liquid / methods
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Diagnosis, Differential
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Extracellular Matrix / chemistry
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Extracellular Matrix Proteins / cerebrospinal fluid
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Extracellular Matrix Proteins / genetics
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Extracellular Matrix Proteins / isolation & purification
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Humans
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Immunoglobulins / cerebrospinal fluid
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Immunoglobulins / genetics
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Immunoglobulins / isolation & purification
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Inflammation
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Middle Aged
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Motor Neuron Disease / cerebrospinal fluid
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Motor Neuron Disease / diagnosis*
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Motor Neuron Disease / genetics
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Motor Neuron Disease / pathology
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Proteome / genetics
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Proteome / isolation & purification*
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Proteome / metabolism
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Proteomics / methods
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Sensitivity and Specificity
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Support Vector Machine
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Synapses / genetics
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Synapses / metabolism
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Synaptic Transmission
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Tandem Mass Spectrometry / methods
Substances
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APLP1 protein, human
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Adaptor Proteins, Signal Transducing
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Amyloid beta-Protein Precursor
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Biomarkers
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CADM3 protein, human
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Calcium-Binding Proteins
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Cell Adhesion Molecules
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Cerebrospinal Fluid Proteins
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Extracellular Matrix Proteins
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Immunoglobulins
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Proteome
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SPARCL1 protein, human