NFASC - neurofascin | Elisa - Clia - Antibody - Protein

Background

Neurofascin (NFASC) is a cell adhesion molecule crucial for the development and maintenance of the nervous system. It is part of the L1 family of cell adhesion molecules, which are integral membrane proteins involved in cell-cell adhesion processes. Neurofascin plays a pivotal role in the formation and function of the nodes of Ranvier and the initial segments of axons, both of which are critical for the proper conduction of electrical impulses along neurons. The NFASC gene, located on chromosome 1q32.1, encodes several isoforms of neurofascin through alternative splicing. These isoforms have distinct but overlapping functions in neural development and synaptic plasticity.

Protein Structure

Neurofascin is a multi-domain protein characterized by the following structural features:

1. Immunoglobulin (Ig) Domains: Neurofascin contains six Ig-like domains at its N-terminal. These domains are involved in homophilic (self-binding) and heterophilic (binding to other molecules) interactions, essential for cell adhesion and signaling.
2. Fibronectin Type III (FNIII) Domains: It has five FNIII domains that contribute to the structural stability of the protein and its interactions with other cell adhesion molecules and the extracellular matrix.
3. Mucin-like Domain: This domain is rich in serine and threonine residues and is heavily glycosylated. It plays a role in cell signaling and protection against proteolytic enzymes.
4. Transmembrane Domain: This single-pass transmembrane domain anchors neurofascin to the cell membrane, facilitating its role as a receptor and adhesion molecule.
5. Cytoplasmic Tail: The intracellular domain of neurofascin interacts with cytoskeletal and signaling proteins, crucial for its role in node of Ranvier and axon initial segment formation.

Classification and Subtypes

Neurofascin has several isoforms generated through alternative splicing, with two major isoforms being:

1. Neurofascin-186 (NF186): This isoform is predominantly expressed at the nodes of Ranvier and the axon initial segments. It plays a critical role in the clustering of voltage-gated sodium channels, essential for action potential propagation.
2. Neurofascin-155 (NF155): This isoform is primarily found in the paranodal regions, where it interacts with contactin and Caspr (contactin-associated protein) to form the paranodal junctions that insulate and separate the nodes of Ranvier.

Function and Biological Significance

Neurofascin is essential for several key processes in the nervous system:

1. Node of Ranvier Formation: NF186 is critical for the assembly and maintenance of the nodes of Ranvier, which are gaps in the myelin sheath that facilitate rapid saltatory conduction of nerve impulses.
2. Axon Initial Segment: NF186 also plays a vital role in the clustering of sodium channels at the axon initial segment, the site where action potentials are initiated.
3. Paranodal Junctions: NF155 is involved in the formation of paranodal junctions, which help maintain the integrity of the nodes of Ranvier and prevent current leakage during nerve impulse transmission.
4. Synaptic Plasticity: Neurofascin contributes to synaptic plasticity, influencing learning and memory processes by modulating synapse formation and stability.
5. Neuronal Development: During development, neurofascin is crucial for neuron-neuron and neuron-glia interactions, guiding axonal growth and ensuring proper neural circuit formation.

Clinical Issues

Mutations and dysregulation of NFASC are associated with various neurological disorders:

1. Autoimmune Neuropathies: Autoantibodies targeting neurofascin isoforms, particularly NF186, are implicated in autoimmune neuropathies such as Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy (CIDP).
2. Multiple Sclerosis (MS): Neurofascin disruption has been linked to MS, where demyelination and loss of nodes of Ranvier contribute to the disease's pathology.
3. Hereditary Neuropathies: Genetic mutations in NFASC can lead to hereditary neuropathies, characterized by muscle weakness, sensory loss, and impaired motor function.
4. Cognitive Disorders: Given neurofascin’s role in synaptic plasticity, alterations in its function or expression are associated with cognitive disorders, including intellectual disability and autism spectrum disorders.

Summary

Neurofascin (NFASC) is a crucial cell adhesion molecule involved in the development and maintenance of the nervous system. It is integral to the formation of the nodes of Ranvier and the axon initial segment, both essential for the rapid conduction of nerve impulses. Neurofascin's multiple domains enable it to interact with various proteins, contributing to its roles in neural adhesion, signaling, and synaptic plasticity. The two major isoforms, NF186 and NF155, have distinct functions in these processes. Dysregulation of neurofascin is linked to several neurological disorders, highlighting its importance in maintaining neural integrity and function. Understanding neurofascin’s structure and function is crucial for developing therapeutic strategies for related neuropathies and cognitive disorders.