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

Abstract

AbstractIncreased and decreased dosage of thePeripheral Myelin Protein 22(PMP22) gene cause dysmyelinating peripheral neuropathy. Charcot-Marie-Tooth Disease Type 1A (CMT1A,PMP22duplication) and Hereditary Neuropathy with Liability to Pressure Palsies (HNPP,PMP22deletion) are the most common inherited peripheral neuropathies, yet gaps remain about their pathophysiology and pathomechanims. Our previous results with CMT1A model mice demonstrate that muscle atrophy occurs without evidence of secondary axon degeneration suggesting that primary myelin dysfunction may contribute to functional deficits in CMT1A and motivating investigation of myelin dysfunction. Here we used CMT1A and HNPP model mice and confocal immunofluorescence imaging of teased tibial nerve fibers to determine how altered PMP22 expression disrupts myelin integrity and reveal CMT1A and HNPP pathomechanisms. We identified dramatic changes to molecular machinery at Schmidt-Lanterman incisures (SLIs) and Nodes of Ranvier that led us to propose two potential pathomechanisms for CMT1A and HNPP: impaired metabolic support and axonal ion disequilibrium. We also developed a working model for these pathomechanims that is driven by PMP22-mediated regulation of adherens junctions. Ongoing studies are aimed at testing these proposed pathomechanisms and determining how altered PMP22 and adherens junctions cause these defects. This work will provide insight into CMT1A and HNPP pathogenesis and may reveal novel approaches for developing therapeutics.