Impact of Neurofascin on Chronic Inflammatory Demyelinating Polyneuropathy via Changing the Node of Ranvier Function: A Review

Abstract

The effective conduction of action potential in the peripheral nervous system depends on the structural and functional integrity of the node of Ranvier and paranode. Neurofascin (NF) plays an important role in the conduction of action potential in a saltatory manner. Two subtypes of NF, NF186, and NF155, are involved in the structure of the node of Ranvier. In patients with chronic inflammatory demyelinating polyneuropathy (CIDP), anti-NF antibodies are produced when immunomodulatory dysfunction occurs, which interferes with the conduction of action potential and is considered the main pathogenic factor of CIDP. In this study, we describe the assembling mechanism and anatomical structure of the node of Ranvier and the necessary cell adhesion molecules for its physiological function. The main points of this study are that we summarized the recent studies on the role of anti-NF antibodies in the changes in the node of Ranvier function and its impact on clinical manifestations and analyzed the possible mechanisms underlying the pathogenesis of CIDP.

Anti-pan-neurofascin antibodies induce subclass-related complement activation and nodo-paranodal damage

“…We now provide additional insights by performing co-staining with a commercial anti-pan-neurofascin antibody, and could clearly show that low paranodal binding is not caused by immediate neurofascin-155 degradation or diffusion, but in fact by a low accessibility to the paranode that is protected by the terminal myelin loops and thus less exposed than nodal neurofascin-186. 19 , 48 This direct access of anti-pan-neurofascin antibodies to nodal targets in comparison to anti-neurofascin-155 could contribute to the acute and more severe phenotype of pan-neurofascin-associated disease. However, the binding strongly depended on the autoantibody titre.…”

Pan-Neurofascin autoimmune nodopathy – a life-threatening, but reversible neuropathy

“…At the juxtaparanode, voltage-gated potassium channels are clustered. At the paranode, the axoglial protein complex of NF155, Contactin-1 and Caspr1 attaches the terminal myelin loops of the myelinating Schwan cell to the axonal cyotskeleton, which is crucial for maintaining the nodal architecture and physiological signal transduction [35]. At the nodal gap, voltage-gated sodium channels are highly enriched and secured to the axonal cytoskeleton by cell adhesion molecules such as Neurofascin-186 (NF186) and glial matrix proteins [35].…”

“…Thus, neurofascin plays a crucial role in several compartments of the node of Ranvier. This cell adhesion molecule belongs to the L1 group within the immunoglobulin superfamily [35]. Due to alternative splicing, various isoforms have been described, such as NF140, NF155, NF166, NF180, and NF186, which all share six common Immunoglobulin-like domains (6Ig) and a transmembrane domain but differ in the composition of their fibronectin domains (see Fig.…”

“…The anatomy of the node of Ranvier is crucial for saltatory conduction. Several recent reviews and ultrastructural studies highlight its molecular features [33–35,36 ▪ ]. In brief, the node of Ranvier is separated into three compartments: The node, paranode and juxtaparanode (see Fig.…”

“…Due to alternative splicing, various isoforms have been described, such as NF140, NF155, NF166, NF180, and NF186, which all share six common Immunoglobulin-like domains (6Ig) and a transmembrane domain but differ in the composition of their fibronectin domains (see Fig. 1) [35]. NF140, NF166, and NF180 are expressed during neural embryonic development, whereas NF155 and NF186 are of major importance for the stability and function of the mature peripheral node of Ranvier [35,37].…”