Schwann cell autophagy, myelinophagy, initiates myelin clearance from injured nerves.
Bottom Line: Myelinophagy was positively regulated by the Schwann cell JNK/c-Jun pathway, a central regulator of the Schwann cell reprogramming induced by nerve injury.We also present evidence that myelinophagy is defective in the injured central nervous system.These results reveal an important role for inductive autophagy during Wallerian degeneration, and point to potential mechanistic targets for accelerating myelin clearance and improving demyelinating disease.
Affiliation: Department of Cell and Developmental Biology, University College London, London WC1E 6BT, England, UK.Show MeSH
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Mentions: If Schwann cells degrade myelin by autophagy, autophagy inhibitors should reduce myelin breakdown. We therefore cultured nerve segments with the widely used autophagy inhibitors 3-methyladenine (3-MA) and Bafilomycin A1 (Klionsky et al., 2012). The lysosomal inhibitor NH4Cl was included for comparison. These inhibitors strikingly prevented the degradation of the myelin proteins MPZ and MBP in nerve segments maintained in vitro for 5 d but not in uncut nerve segments, indicating that autophagy is required for myelin protein breakdown (Fig. 3 A). This was not due to transcriptional changes, as we did not find significant differences in mRNA levels in nerve segments treated with these autophagy inhibitors (Fig. 3 B). Histologically, we found that 3-MA reduced myelin collapse in cultured nerves compared with control nerves, in which most sheaths appeared as collapsed whorls (Fig. 3 C).
Affiliation: Department of Cell and Developmental Biology, University College London, London WC1E 6BT, England, UK.