Autophagic myelin destruction by schwann cells during wallerian degeneration and segmental demyelination

Abstract

As lysosomal hydrolysis has long been suggested to be responsible for myelin clearance after peripheral nerve injury, in this study, we investigated the possible role of autophagolysosome formation in myelin phagocytosis by Schwann cells and its final contribution to nerve regeneration. We found that the canonical formation of autophagolysosomes was induced in demyelinating Schwann cells after injury, and the inhibition of autophagy via Schwann cell-specific knockout of the atg7 gene or pharmacological intervention of lysosomal function caused a significant delay in myelin clearance. However, Schwann cell dedifferentiation, as demonstrated by extracellular signal-regulated kinase activation and c-Jun induction, and redifferentiation were not significantly affected, and thus the entire repair program progressed normally in atg7 knockout mice. Finally, autophagic Schwann cells were also found during segmental demyelination in a mouse model of inflammatory peripheral neuropathy. Together, our findings suggest that autophagy is the self-myelin destruction mechanism of Schwann cells, but mechanistically, it is a process distinct from Schwann cell plasticity for nerve repair.

Schwann cells use TAM receptor-mediated phagocytosis in addition to autophagy to clear myelin in a mouse model of nerve injury

“…GomezSanchez et al recently demonstrated that Schwann cells use autophagy to degrade myelin after nerve transection, a process they coined "myelinophagy" (22). These findings were supported in a subsequent publication by Jang et al (20). Given the known association between nutrient restriction and autophagy and the more drastic disruption in distal nerve blood supply caused by transection injury in comparison with crush injury, we wondered if these findings would apply in a nerve crush scenario as well (30).…”

“…To test whether autophagy is necessary for Schwann cell degradation of myelin after nerve crush injury, as has recently been shown after nerve transection, we generated mice in which Schwann cells are unable to perform autophagy due to deletion of essential autophagy protein atg7 (floxed Atg7 × P0 Cre) (20)(21)(22). These mice did not display any obvious behavioral abnormalities before their use for experiments at 8 to 12 wk of age.…”

Longitudinal study of neuropathy, microangiopathy, and autophagy in sural nerve: Implications for diabetic neuropathy

“…Although not significant, the proportion of autophagy structures had also decreased in unmyelinated axons while it was increased in Schwann cells at follow-up. Indeed, it has recently been reported that Schwann cells use autophagy as a degradation process (Gomez-Sanchez et al, 2015;Jang et al, 2016). Obviously, the autophagy pathway is affected in both axons and Schwann cells in longterm diabetes.…”

Ingenuity Pathway Analysis of Gene Expression Profiles in Distal Nerve Stump following Nerve Injury: Insights into Wallerian Degeneration

“…We have previously reported on the up-regulation of the mRNA expression of BDNF at 1, 4, 7, and 14 days post nerve crush injury (Yi et al, 2016). It has been known that after peripheral nerve injury, Schwann cells not only proliferate to form the bands of Bungner, but also produce a range of neurotrophic factors, including BDNF (Frostick et al, 1998; Faroni et al, 2013; Jang et al, 2016). Therefore, the up-regulated BDNF in the distal nerve stump would augment axonal regrowth and promote nerve regeneration.…”