Remyelination protects axons from demyelination-associated axon degeneration.
In multiple sclerosis, demyelination of the CNS axons is associated with axonal injury and degeneration, which is now accepted as the major cause of neurological disability in the disease. Although the kinetics and the extent of axonal damage have been described in detail, the mechanisms by which it occurs are as yet unclear; one suggestion is failure of remyelination. The goal of this study was to test the hypothesis that failure of prompt remyelination contributes to axonal degeneration following demyelination. Remyelination was inhibited by exposing the brain to 40 Gy of X-irradiation prior to cuprizone intoxication and this resulted in a significant increase in the extent of axonal degeneration and loss compared to non-irradiated cuprizone-fed mice. To exclude the possibility that this increase was a consequence of the X-irradiation and to highlight the significance of remyelination, we restored remyelinating capacity to the X-irradiated mouse brain by transplanting of GFP-expressing embryo-derived neural progenitors. Restoring the remyelinating capacity in these mice resulted in a significant increase in axon survival compared to non-transplanted, X-irradiated cuprizone-intoxicated mice. Our results support the concept that prompt remyelination protects axons from demyelination-associated axonal loss and that remyelination failure contributes to the axon loss that occurs in multiple sclerosis.
Irvine
K A
KA
Department of Veterinary Medicine, MS Society Cambridge Centre for Myelin Repair, Madingley Road, Cambridge, CB3 OES, UK. karen.irvine@ucsf.edu
Blakemore
W F
WF
D000818:Animals; D001369:Axons / Q000473:pathology*; D003337:Corpus Callosum / Q000473:pathology; D003471:Cuprizone; D003711:Demyelinating Diseases; D038524:Diffusion Magnetic Resonance Imaging; D005260:Female; D049452:Green Fluorescent Proteins / Q000032:analysis; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D023421:Models, Animal; D009103:Multiple Sclerosis / Q000473:pathology / Q000503:physiopathology*; D009186:Myelin Sheath / Q000502:physiology*; D009410:Nerve Degeneration / Q000473:pathology / Q000503:physiopathology; D009416:Nerve Regeneration; D033581:Stem Cell Transplantation; D014965:X-Rays
D049452:Green Fluorescent Proteins; D003471:Cuprizone