Proteasome inhibition suppresses Schwann cell dedifferentiation in vitro and in vivo

Abstract

The ubiquitin-proteasome system (UPS), lysosomes, and autophagy are essential protein degradation systems for the regulation of a variety of cellular physiological events including the cellular response to injury. It has recently been reported that the UPS and autophagy mediate the axonal degeneration caused by traumatic insults and the retrieval of nerve growth factors. In the peripheral nerves, axonal degeneration after injury is accompanied by myelin degradation, which is tightly related to the reactive changes of Schwann cells called dedifferentiation. In this study, we examined the role of the UPS, lysosomal proteases, and autophagy in the early phase of Wallerian degeneration of injured peripheral nerves. We found that nerve injury induced an increase in the ubiquitin conjugation and lysosomal-associated membrane protein-1 expression within 1 day without any biochemical evidence for autophagy activation. Using an ex vivo explant culture of the sciatic nerve, we observed that inhibiting proteasomes or lysosomal serine proteases prevented myelin degradation, whereas this was not observed when inhibiting autophagy. Interestingly, proteasome inhibition, but not leupeptin, prevented Schwann cells from inducing dedifferentiation markers such as p75 nerve growth factor receptor and glial fibrillary acidic protein in vitro and in vivo. In addition, proteasome inhibitors induced cell cycle arrest and cellular process formation in cultured Schwann cells. Taken together, these findings indicate that the UPS plays a role in the phenotype changes of Schwann cells in response to nerve injury.

Extrinsic cellular and molecular mediators of peripheral axonal regeneration

“…In the very early phase of Wallerian degeneration, Schwann cells are able to respond to injury with changes of their phenotype at least in part by means of their intracellular ubiquitin-proteasome system (UPS) (Saitoh and Araki 2010;Lee et al 2009). Further, the rapid activation (within 1 h post injury) of the receptor tyrosine kinase receptor erbB2 by axonal neuregulin results in the activation of the mitogen-activated protein kinase (MAPK).…”

Mammalian Cell Dedifferentiation as a Possible Outcome of Stress

“…It is possible that stressful environments dictate cells' epigenetic modulation and, in so doing, alter gene expression. It is also possible that altered protein regulation, by means of phosphorylation or degradation, might be involved in cell reprogramming [23]. Importantly, experimentally prepared iPS cells have dedifferentiated almost all the way to the ESC state: i.e., to embryonic pluripotency.…”

Role of macrophages in Wallerian degeneration and axonal regeneration after peripheral nerve injury

“…Schwann cells play an important role in the early stage of Wallerian degeneration. Upon injury, Schwann cells begin to de-differentiate in the distal nerve depending on the ubiquitin-proteasome system [59], a process that alters the gene expression profile of Schwann cells and provides an environment for axonal degeneration [38, 59,76]. Schwann cells are able to remove myelin debris, a component that functions as a barrier to axon regrowth and contains axonal growth inhibitory signals including myelin-associated glycoprotein [38,48].…”