Paranodes

Paranodes are specialized axonal domains located flanking each node of Ranvier in myelinated peripheral and central nervous system fibers. They are formed where the terminal loops of the myelin sheath attach to the axolemma, creating septate-like junctions that separate the node from the adjacent internodal myelin. The paranodal region, typically 1–2 µm in length on either side of the node, is critical for maintaining the segregation of ion channels that underlies salt‑saltate conduction.

Molecularly, paranodes are defined by a tripartite complex of contactin‑associated protein (Caspr), contactin‑1, and neurofascin‑155, which are expressed on the axonal and glial membranes respectively. These proteins assemble into transverse bands that tether the glial loops to the axon, establishing a diffusion barrier that restricts the lateral movement of voltage‑gated sodium channels in the node and potassium channels in the juxtaparanode. The precise organization of these components is orchestrated during myelination by oligodendrocytes in the CNS and Schwann cells in the PNS.

Developmentally, paranodal junctions appear after initial myelin wrapping and mature throughout the first post‑natal weeks. Disruption of paranodal proteins in animal models leads to loss of nodal polarity, slowed conduction velocity, and neurological deficits. In humans, mutations in CASPR1, CNTN1, or NFASC are associated with inherited neuropathies and demyelinating disorders, while autoimmune antibodies targeting paranodal antigens have been implicated in some forms of peripheral neuropathy.

Research continues to explore how paranodal integrity influences axonal health, regeneration, and the pathogenesis of disorders such as multiple sclerosis, highlighting the domain’s importance beyond its structural role in rapid nerve impulse propagation.