Proteasome inhibition suppresses Schwann cell dedifferentiation in vitro and in vivo.
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.
Lee
Hyun Kyoung
HK
Department of Physiology, Medical Science Research Institute, College of Medicine, Dong-A University, Seo-Gu, Busan, South Korea.
Shin
Yoon Kyung
YK
Jung
Junyang
J
Seo
Su-Yeong
SY
Baek
Sun-Yong
SY
Park
Hwan Tae
HT
D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000502:physiology; D019771:Axotomy; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D054337:Cell Dedifferentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D007091:Image Processing, Computer-Assisted; D007976:Leupeptins / Q000494:pharmacology; D052118:Lysosomal-Associated Membrane Protein 1 / Q000378:metabolism; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009413:Nerve Fibers, Myelinated / Q000187:drug effects / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D012583:Schwann Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D012584:Sciatic Nerve / Q000166:cytology / Q000187:drug effects / Q000293:injuries / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects* / Q000502:physiology; D014855:Wallerian Degeneration / Q000378:metabolism
D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D052118:Lysosomal-Associated Membrane Protein 1; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde