Reduced raft-association of NF155 in active MS-lesions is accompanied by the disruption of the paranodal junction.
Neurofascin155 (NF155) is required for the establishment of the paranodal axo-glial junction, the predominant interaction site between myelin and axon. It has been shown that the distribution of NF155 is altered in demyelinating diseases such as multiple sclerosis (MS). However, little is known about the biochemical mechanisms underlying these changes. We therefore compared NF155 in postmortem tissue of active and chronic inactive MS lesions with white matter from healthy controls. Although NF155 showed a very similar expression in all control white matter samples, a strong individual variation was observed in MS-lesions with NF155-levels reduced in most samples. At the same time an NF155-fragment was increased in MS-lesions, suggesting that NF155 is subject to protein degradation in lesion sites. Interestingly, the association of NF155 to membrane microdomains (rafts) was reduced in all lesions, irrespective of the amount of NF155, indicating that membrane association of NF155 was generally affected. Therefore, myelin fractionation experiments were performed to analyze the fate of paranodal proteins during demyelination. Although NF155 was enriched in heavy myelin from both control white matter and active MS-lesions, association of Caspr1/paranodin with heavy myelin was abolished in MS-lesions, demonstrating that paranodal junctions are disrupted. In conclusion, the data support the hypothesis that efficient raft-association of NF155 is essential for the assembly of the paranodal junction and demonstrate that reduced association of NF155 to lipid rafts is accompanied by the disassembly of the paranodal junction and thus contributes to the demyelination process in MS.
Maier
Olaf
O
Department of Cell Biology/Section Membrane Cell Biology, University Medical Center Groningen, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands. o.maier@med.umcg.nl
Baron
Wia
W
Hoekstra
Dick
D
D000818:Animals; D000831:Animals, Newborn; D015815:Cell Adhesion Molecules / Q000737:chemistry / Q000378:metabolism*; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism; D002458:Cell Fractionation; D002478:Cells, Cultured; D003711:Demyelinating Diseases / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D021962:Membrane Microdomains / Q000378:metabolism*; D008970:Molecular Weight; D009103:Multiple Sclerosis / Q000378:metabolism* / Q000473:pathology*; D009413:Nerve Fibers, Myelinated / Q000378:metabolism / Q000473:pathology; D009414:Nerve Growth Factors / Q000737:chemistry / Q000378:metabolism*; D009836:Oligodendroglia / Q000166:cytology / Q000378:metabolism; D011901:Ranvier's Nodes / Q000378:metabolism* / Q000473:pathology*; D051381:Rats; D017208:Rats, Wistar; D013107:Sphingolipids / Q000378:metabolism
C491323:CNTNAP1 protein, human; D015815:Cell Adhesion Molecules; D015816:Cell Adhesion Molecules, Neuronal; C054305:NFASC protein, human; D009414:Nerve Growth Factors; D013107:Sphingolipids