Carty, LM; (2013) The Role of Autophagy in Peripheral Nerve Injury. Doctoral thesis , UCL (University College London).

Abstract

Nerve transection injury leads to Wallerian degeneration, involving axonal breakdown, Schwann cell demyelination and Schwann cell transdifferentiation to the Bungner repair cell. Schwann cells participate in demyelination in two ways: indirectly through recruitment of blood-borne phagocytic macrophages and also by a direct, intrinsic mechanism of myelin fragmention and digestion. The lysosome has been implicated in Schwann cell myelin digestion but vesicle pathways in Schwann cells have not been thoroughly investigated. Autophagy is a lysosome-dependent, vesicular degradation pathway directed towards bulk intracellular proteins and was investigated in this study as a potential mechanism for Schwann cell mediated demyelination. Autophagy was found to be strongly induced in response to nerve injury, concomitant with the onset of Schwann cell mediated demyelination, in vitro and in vivo. Autophagy levels were down regulated once demyelination was complete. The expression pattern of GFP-LC3 confirmed that Schwann cells formed autophagosomes in response to nerve injury. Inhibition of autophagy in Schwann cells using pharmacological inhibitors and Atg7fl=flP0-cre mice led to a severe defect in demyelination in response to injury, in vitro and in vivo. Myelin protein and lipid degradation as a marker for demyelination was strikingly reduced in the absence of Schwann cell autophagy and the emergence of structural demyelination features was also delayed. Myelin vesicles were found to accumulate ULK1 in Atg7 null Schwann cells. Myelin vesicles were also shown to be surrounded by GFP-LC3 autophagosomes and it is therefore proposed that the interaction of ULK1 and myelin leads to the formation of autophagosomes on myelin vesicles, which would result in subsequent delivery of myelin to the lysosome. Demyelination-associated autophagy was shown to be promoted by the Schwann cell JNK/c-Jun pathway. Autophagy was shown to be misregulated in a mouse model of demyelinating peripheral neuropathy. In addition, CNS nerve fibers were found not to induce autophagy during demyelination in vitro. Autophagy is therefore likely to be an important determinant of demyelination in the PNS and may represent a differential response to injury between the PNS and CNS.

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