Metastable axons by mitochondrial-SARM1 feedback loop in CMT2B sensory neuropathy

Mutations in Rab7a GTPase (RAB7A) cause the development of hereditary peripheral axonal neuropathy, referred to as Charcot-Marie-Tooth disease 2B (CMT2B). Disturbances in cellular organelle dynamics, such as autophagy, endosomal trafficking, and mitochondrial homeostasis, are related to the pathogenesis of CMT2B. However, the mechanism by which these processes evoke axonal neuropathy in peripheral sensory neurons remains unclear. Here, we demonstrated that RAB7A L129F elicited mitochondrial oxidative stress-mediated activation of Sterile alpha and TIR motif-containing protein 1 (SARM1), the critical executor of Wallerian degeneration, in dorsal root ganglion (DRG) neurons. In addition, SARM1 exacerbated mitochondrial ROS generation, indicating the presence of a feedback loop of the mitochondrial-SARM1 axis. However, activation of the mitochondrial stress-SARM1 axis by RAB7A L129F only caused metastable axons, structurally unstable axons that did not proceed to axonal fragmentation, due to NAD + decrease without intra-axonal ATP depletion. We observed that RAB7A L129F -induced autophagy activation inhibited the progression of metastable axons to axon degeneration by inhibiting mitochondrial-SARM1 feedback loop in DRG neurons. Finally, peripheral sensory neuron-specific transduction of adeno-associated virus of RAB7A L129F in mice developed abnormal pain sensation with the degeneration of intraepidermal nerve fibers in footpads with a SARM1-dependent manner. Our research identified a mitochondrial-SARM1 positive feedback loop driving a metastable axonal state in a cellular model of CMT2B-type neuropathy and showed that autophagy plays a negative regulatory role in the feedback loop to prevent the development of severe axonal degeneration.