Full-length and fragmented netrin-1 in multiple sclerosis plaques are inhibitors of oligodendrocyte precursor cell migration

Jenea M Bin, Sathyanath Rajasekharan, Tanja Kuhlmann, Ilana Hanes, Nathalie Marcal, Dong Han, Sonia P Rodrigues, Soo Yuen Leong, Jia Newcombe, Jack P Antel, Timothy E Kennedy

Research output: Contribution to journalArticlepeer-review

Abstract

Oligodendrocytes exhibit a limited capacity to remyelinate in multiple sclerosis. Factors present in multiple sclerosis lesions are thought to inhibit oligodendrocyte precursor cell migration, limiting their recruitment to axons requiring remyelination; however, few inhibitors have been identified. A candidate inhibitor is netrin-1, a secreted protein that repels migrating oligodendrocyte precursor cells during neural development and is expressed by myelinating oligodendrocytes in the mature rodent central nervous system. Herein, we examined the distribution of netrin-1 in adult human white matter and multiple sclerosis lesions. We detected full-length netrin-1 protein and shorter netrin-1 fragments in samples of normal white matter and of multiple sclerosis lesions from adult human brain. We demonstrate that peptides corresponding to amino terminal domains VI and V of netrin-1 repel migrating oligodendrocyte precursor cells, but lack the chemoattractant activity of full-length netrin-1. Furthermore, recombinant domains VI-V of netrin-1 disrupt the chemoattractant activity of full-length netrin-1, consistent with a competitive mechanism of action. These findings indicate that full-length and fragmented forms of netrin-1, found in multiple sclerosis lesions, have the capacity to inhibit oligodendrocyte precursor migration, identifying netrin-1 as a potential target for therapies that promote remyelination.

Original languageEnglish
Pages (from-to)673-80
Number of pages8
JournalAmerican Journal of Pathology
Volume183
Issue number3
DOIs
Publication statusPublished - Sep 2013

Keywords

  • Adult
  • Aged
  • Animals
  • Brain
  • Cell Movement
  • Chickens
  • Child
  • Female
  • HEK293 Cells
  • Humans
  • Male
  • Middle Aged
  • Multiple Sclerosis
  • Nerve Growth Factors
  • Oligodendroglia
  • Peptide Fragments
  • Protein Structure, Tertiary
  • Rats
  • Rats, Sprague-Dawley
  • Stem Cells
  • Tumor Suppressor Proteins

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