Schwann cell p75 neurotrophin receptor modulates small fiber degeneration in diabetic neuropathy

Abstract Diabetic neuropathy has an incidence as high as 50% of diabetic patients and is characterized by damage to neurons, Schwann cells and blood vessels within the peripheral nervous system. The low‐affinity neurotrophin receptor p75 (p75 NTR ), particularly expressed by the Schwann cells in the peripheral nerve, has previously been reported to play a role in developmental myelination and cell survival/death. Increased levels of p75 NTR , in the endoneurium and plasma from diabetic patients and rodent models of disease, have been observed, proposing that this receptor might be involved in the pathogenesis of diabetic neuropathy. Therefore, in this study, we addressed this hypothesis by utilizing a mouse model of selective nerve growth factor receptor ( Ngfr ) deletion in Schwann cells (SC‐p75 NTR ‐KO). Electron microscopy of sciatic nerves from mice with high fat diet induced obesity demonstrated how loss of Schwann cell–p75 NTR aggravated axonal atrophy and loss of C‐fibers. RNA sequencing disclosed several pre‐clinical signaling alterations in the diabetic peripheral nerves, dependent on Schwann cell p75 NTR signaling, specially related with lysosome, phagosome, and immune pathways. Morphological and biochemical analyses identified abundant lysosomes and autophagosomes in the C‐fiber axoplasm of the diabetic SC‐p75 NTR ‐KO nerves, which together with increased Cathepsin B protein levels corroborates gene upregulation from the phagolysosomal pathways. Altogether, this study demonstrates that Schwann cell p75 NTR deficiency amplifies diabetic neuropathy disease by triggering overactivation of immune‐related pathways and increased lysosomal stress.