Label-free LC-MS/MS proteomic analysis of cerebrospinal fluid identifies protein/pathway alterations and candidate biomarkers for amyotrophic lateral sclerosis

Mahlon A. Collins, Jiyan An, Brian L. Hood, Thomas P. Conrads, Robert P. Bowser

Research output: Contribution to journalArticle

37 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)4486-4501
Number of pages16
JournalJournal of Proteome Research
Volume14
Issue number11
DOIs
StatePublished - Nov 6 2015

Keywords

  • LC-MS/MS
  • amyotrophic lateral sclerosis
  • biomarker
  • cerebrospinal fluid
  • extracellular matrix
  • liquid chromatography-tandem mass spectrometry
  • mass spectrometry
  • proteomics

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