title: Full-length and fragmented netrin-1 in multiple sclerosis plaques are inhibitors of oligodendrocyte precursor cell migration.
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.
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.
authors.forename: Jenea M
authors.initials: JM
authors.lastname: Bin
authors.forename: Sathyanath
authors.initials: S
authors.lastname: Rajasekharan
authors.forename: Tanja
authors.initials: T
authors.lastname: Kuhlmann
authors.forename: Ilana
authors.initials: I
authors.lastname: Hanes
authors.forename: Nathalie
authors.initials: N
authors.lastname: Marcal
authors.forename: Dong
authors.initials: D
authors.lastname: Han
authors.forename: Sonia P
authors.initials: SP
authors.lastname: Rodrigues
authors.forename: Soo Yuen
authors.initials: SY
authors.lastname: Leong
authors.forename: Jia
authors.initials: J
authors.lastname: Newcombe
authors.forename: Jack P
authors.initials: JP
authors.lastname: Antel
authors.forename: Timothy E
authors.initials: TE
authors.lastname: Kennedy
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement; D002645:Chickens; D002648:Child; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000378:metabolism* / Q000473:pathology*; D009414:Nerve Growth Factors / Q000737:chemistry / Q000378:metabolism*; D000075388:Netrin-1; D009836:Oligodendroglia / Q000378:metabolism* / Q000473:pathology*; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051381:Rats; D017207:Rats, Sprague-Dawley; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology*; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; C000617354:Ntn1 protein, rat; D010446:Peptide Fragments; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1