Aberrant Molecular Myelin Architecture in Charcot-Marie-Tooth Disease Type 1A and Hereditary Neuropathy With Liability to Pressure Palsies.

Charcot-Marie-Tooth Disease Type 1A (CMT1A) and Hereditary Neuropathy with Liability to Pressure Palsies (HNPP) are the most common inherited peripheral neuropathies and arise from copy number variation of the Peripheral Myelin Protein 22 (PMP22) gene. While secondary axon degeneration has been proposed as the primary driver of disability, our prior work demonstrated pronounced neuromuscular impairment in CMT1A model mice in the absence of overt axonal loss, prompting investigation into primary myelin dysfunction. Here, we reveal that altered PMP22 dosage profoundly disrupts molecular architecture at critical myelin domains, Schmidt-Lanterman incisures (SLIs) and Nodes of Ranvier. Using high-resolution confocal imaging of teased peripheral nerve fibers from CMT1A and HNPP model mice, we identified widespread disorganization of adherens junctions, mislocalization of Connexin29 and aberrant distribution of nodal ion channels, with several defects more severe in CMT1A, consistent with disease burden. Notably, nodal widening and abnormal spreading of Kv1.2 and Caspr along internodes indicate compromised axo-glial compartmentalization essential for saltatory conduction. Together, these findings support a model in which PMP22 functions as a structural organizer of myelin, coordinating adherens junction patterning and nodal subdomain integrity. Dysregulation of this function is predicted to compromise Schwann-cell architecture, metabolic support and axonal excitability. Our findings support a paradigm shift in which molecular destabilization of myelin, rather than secondary axonal degeneration alone, contributes to disease progression in CMT1A and HNPP. This work also identifies junctional complexes as potential actionable molecular targets and establishes a mechanistic framework applicable to a broad spectrum of inherited dysmyelinating and acquired demyelinating neuropathies.