DNM2 -Charcot-Marie-Tooth neuropathy stems from disrupted Schwann cell function and shows limited therapeutic reversibility

Abstract Dominant loss-of-function mutations in DNM2 cause Charcot-Marie-Tooth neuropathy characterized by sensory and motor deficits associated with myelin and/or axonal abnormalities and muscle atrophy. Increasing DNM2 activity from embryogenesis has been reported to ameliorate neuromuscular phenotypes in the Dnm2K562E/+ Charcot-Marie-Tooth mouse; however, this model displays predominantly muscle pathology and limited nerve involvement, precluding rigorous evaluation of neuropathic mechanisms and potential therapies. Here, we performed comprehensive behavioral, electrophysiological, histological and molecular analyses to characterize the Dnm2K562E/SC- mouse, which combines systemic heterozygosity for the common K562E mutation together with Schwann cell-specific deletion of wild-type Dnm2. This model faithfully reproduces key clinical and pathological features of DNM2-Charcot-Marie-Tooth, including motor deficits, reduced general force and coordination, and severe sensory and motor conduction deficits associated with axonal loss, demyelination, and inflammation. Mechanistically, we delineate a coherent pathological sequence that explains the profound functional deficits. In particular, a downregulation of the transcription factor EGR2, a master regulator of myelin gene expression, and of the myelin protein MPZ correlates with demyelination. To evaluate the therapeutic potential of DNM2 supplementation, post-symptomatic intrathecal delivery of AAV9-DNM2 driven by the Schwann cell-specific MPZ promoter was performed at 4 weeks. Although DNM2 expression increased in peripheral nerves (∼1.9-fold), no significant improvements were observed across behavioral, electrophysiological, structural, or molecular parameters. Together, these findings establish the Dnm2K562E/SC- mouse as a robust preclinical model, recapitulating key features of DNM2- Charcot-Marie-Tooth, and provides crucial insight into the biological and temporal constraints that must guide future therapeutic strategies for DNM2-Charcot-Marie-Tooth.