Molecular Myelin Dysfunction in the Most Common Inherited Peripheral Neuropathies - CMT1A and HNPP

Abstract

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 gene (PMP22). While secondary axon degeneration has been proposed as a primary driver of pathogenesis, our prior work demonstrated neuromuscular deficits in CMT1A 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 subdomains, 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 disorganization of adherens junctions, mislocalization of Connexin29, and altered distribution of nodal ion channels in CMT1A and HNPP, with several defects more pronounced in CMT1A, aligning with clinical severity. Notably, Kv1.2 and Caspr mislocalization along the internode and Nav nodal widening suggest disruption of axoglial domains essential for saltatory conduction. Together, these phenotypes support a model in which PMP22 governs myelin architecture, likely through adherens junction regulation, with its dysregulation predicted to impair metabolic support and axonal ion homeostasis, thereby compromising the structural and functional integrity of myelin and contributing directly to disease pathogenesis. These findings shift the pathogenic paradigm for CMT1A and HNPP from axonal degeneration to primary myelin failure and highlight actionable molecular targets for therapeutic intervention. This study offers mechanistic insight into CMT1A and HNPP and provides a conceptual framework with broad relevance to other dysmyelinating disorders. Main PointsO_LIPMP22 copy number variation disrupts myelin architecture at SLIs and Nodes of Ranvier. C_LIO_LIAdherens junction and axoglial domain defects are more severe in CMT1A than HNPP. C_LIO_LIFindings support primary myelin dysfunction as a key driver of pathogenesis. C_LI