Targeting SARM1 improves autophagic stress-induced axonal neuropathy

Abstract

Macroautophagy/autophagy, a lysosome-dependent self-degradative process, is a critical mechanism for the clearance of misfolded proteins and dysfunctional organelles in neurons. In the peripheral nervous system, autophagic stress is associated with the development of peripheral neuropathy. However, the molecular mechanism of axonal neuropathy induced by autophagic stress due to dysfunction of autophagy in peripheral neurons in vivo is still unclear. We found that dorsal root ganglion (DRG) neuron-specific atg7 (autophagy related 7) knockout ( atg7 -cKO) mice employing two different Cre recombinase systems exhibited sensory neuropathy approximately 2 months after birth. In electron microscopy analysis, axon degeneration was clearly observed in the myelinated fibers of the sciatic nerve before the appearance of neuronal cell death. Dystrophic axons filled with abnormal vesicular accumulations and amorphous inclusions were specifically localized in the myelinated axons within the DRG in atg7 -cKO mice, indicating the presence of autophagic stress in proximal axons. In line with the EM findings, the mutant mice showed preferential induction of axonal injury-associated genes, including ATF3 (activating transcription factor 3), in large-size DRG neurons that constitute myelinated fibers without axotomy. SARM1 (sterile alpha and HEAT/Armadillo motif containing 1), the central executioner of Wallerian degeneration, was activated in the sciatic nerves of atg7 -cKO mice, and axonal degeneration and sensory neuropathy in atg7 -cKO mice were prevented via expression of a dominant-negative Sarm1 transgene. Our findings demonstrate the importance of SARM1-dependent axon degeneration in the development of peripheral sensory neuropathy induced by impairment of autophagy. Abbreviations AAV: adeno-associated virus; ATF3: activating transcription factor 3; ATG7: autophagy related 7; AVIL: advillin; cADPR: cyclic ADP ribose; CALC: calcitonin/calcitonin-related polypeptide; CMT: Charcot-Marie-Tooth disease; cKO: conditional knockout; DEG: differentially expressed gene; DRG: dorsal root ganglion; FE-SEM: field emission scanning electron microscopy; IF: immunofluorescence; NCV: nerve conduction velocity; PVALB: parvalbumin; RAG: regeneration-associated gene; ROS: reactive oxygen species; SARM1: sterile alpha and HEAT/Armadillo motif containing 1; SYN1 : synapsin I

Deregulated mitochondrial quality control, the heel of Achilles in elucidating the role of autophagy in SARM1‐mediated axon degeneration

“…Specifically, sterile α and toll/interleukin 1 receptor motif containing protein 1 (SARM1), the central executioner of Wallerian axon degeneration, was activated in the sciatic nerves of Atg7 ‐cKO mice. By contrast, the axonal destruction and sensory neuropathy induced by deletion of Atg7 were prevented via expression of a dominant‐negative Sarm1 transgene, demonstrating that the development of peripheral neuropathy induced by autophagy dysfunction is associated with the SARM1‐dependent core axonal degeneration program (Kim et al., 2023).…”

“…In a recent issue of Autophagy , Kim et al. reported a dorsal root ganglion neuron‐specific Atg7 knockout ( Atg7 ‐cKO) mouse model, which exhibited sensory neuropathy after birth (Kim et al., 2023). This is consistent with previous studies that constitutive autophagy is essential for the maintenance of local homeostasis of axonal compartment (Komatsu et al., 2007) and further clarifies that autophagy impairment in specific neurons is enough to cause axon dysfunction and degeneration.…”