Reduced raft‐association of NF155 in active MS‐lesions is accompanied by the disruption of the paranodal junction

Abstract

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.

Glial and Axonal Pathology in Multiple Sclerosis

“…Early in the disease course and preceding demyelination, changes in the distribution of NF155 have been observed in MS lesions [Vyshkina1 & Kalman, 2008]. Maier et al [2007] showed that the NF155-levels were reduced, suggesting that NF155 is subject to protein degradation in the lesions. On the other hand, studies in sera showed levels significantly higher in patients with chronic progressive forms of MS compared to other inflammatory neurological diseases.…”

Electron tomographic analysis of cytoskeletal cross-bridges in the paranodal region of the node of Ranvier in peripheral nerves

“…In contrast, mitochondria located in the axoplasm outside this region appeared normal, suggesting that the PJB influences mitochondrial function and perhaps transport in the axoplasm of the nodal/paranodal region of myelinated axons of peripheral nerves. The distribution of neurofascin 155 in the glial membrane is altered in one form of multiple sclerosis (MS), a demyelinating disease (Maier et al, 2007). This group discovered that efficient association of neurofascin 155 with lipid raft domains is required for the maintenance of the paranodal axo-glial junction and without this junction, demyelination occurs in MS.…”

Neurofascin as a target for autoantibodies in peripheral neuropathies

“…Antibodies to NF155 found in some patients with AIDP and patients with CIDP could be pathogenic only if their target at the paranodes becomes accessible. Since a disruption of paranodal architecture is a feature of different nerve pathologies such as ischemia and inflammation, 27,28 these antibodies could contribute to the pathology. Anti-NF155 antibodies were reported to inhibit myelination by blocking the formation of the Caspr/contactin/NF155 complex, the core structure at paranodal loops for adhesion between axon and glial cell.…”