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.

Early netrin‐1 expression impairs central nervous system remyelination

“…The specificity of the antibody used on human tissue was previously established. 9 Axons were present in all lesions analyzed (see Fig 1B). In NAWM, the netrin- Fig 1S-U) and Unc5A (see Fig 1V-X) expression was detected, indicating potential chemotropic influence of netrin-1 on adult human OPCs.…”

“…28,29 It has recently been shown that full-length netrin-1 protein and fragments of netrin-1 are found in chronic MS lesions. 9 In addition, netrin-1 has been shown to induce blood vessel remodeling in the subventricular zone following demyelination of the corpus callosum, which allowed for neuroblast emigration toward the lesion. 30 However, the role of netrin-1 in myelin repair remains uninvestigated.…”

“…9 Here, we examined the functional role of netrin-1 in OPC recruitment and myelin repair. We first observed important differences in the patterns of netrin-1 expression detected in MS and experimentally induced lesions that, in contrast to MS, repair myelin efficiently.…”

Truncated netrin-1 contributes to pathological vascular permeability in diabetic retinopathy

“…While full-length netrin-1 has vasoprotective properties (21) and maintains blood-brain barrier function (45), the newly generated fragments contribute to the breakdown of the BRB and thus exacerbate retinal and macular edema. A role for the VI-V fragment of netrin-1 in pathology was previously suggested, given its presence in multiple sclerosis (MS) plaques and capacity to inhibit oligodendrocyte migration (46). While netrin-1 is required for the maintenance of axo-oligodendroglial paranodal junctions (47), ectopic expression of netrin-1 in vivo inhibited remyelination in an experimental model of MS lesions (48).…”

Angiogenesis in multiple sclerosis and experimental autoimmune encephalomyelitis

“…Netrin-1 is a matrix-bound molecule interacting with different receptors (UNC and DCC, certain integrins, DSCAM -Down's syndrome cell adhesion molecule and adenosine receptor AR2b) involved in axon guidance and angiogenic blood vessel guidance [reviewed in 91], that has been shown to inhibit migration of oligodendrocyte precursor cells into the demyelinated lesions [129]. Ephrins and their Eph receptors are short range axon guidance molecules, expressed in developing vessels and critical for their maintenance [reviewed in 91], that have shown different expression profiles in several CNS cytotypes of MS patients [130].…”