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Fortun, J, Dunn, WA Jr, Joy, S, Li, J and Notterpek, L (2003) Emerging role for autophagy in the removal of aggresomes in Schwann cells. J. Neurosci. 23:10672-80


The presence of protein aggregates in the nervous system is associated with various pathological conditions, yet their contribution to disease mechanisms is poorly understood. One type of aggregate, the aggresome, accumulates misfolded proteins destined for degradation by the ubiquitin-proteasome pathway. Peripheral myelin protein 22 (PMP22) is a short-lived Schwann cell (SC) protein that forms aggresomes when the proteasome is inhibited or the protein is overexpressed. Duplication, deletion, or point mutations in PMP22 are associated with a host of demyelinating peripheral neuropathies, suggesting that, for normal SC cell function, the levels of PMP22 must be tightly regulated. Therefore, we speculate that mutant, misfolded PMP22 might overload the proteasome and promote aggresome formation. To test this, sciatic nerves of Trembler J (TrJ) neuropathy mice carrying a leucine-to-proline mutation in PMP22 were studied. In TrJ neuropathy nerves, PMP22 has an extended half-life and forms aggresome-like structures that are surrounded by molecular chaperones and lysosomes. On the basis of these characteristics, we hypothesized that PMP22 aggresomes are transitory, linking the proteasomal and lysosomal protein degradation pathways. Here we show that Schwann cells have the ability to eliminate aggresomes by a mechanism that is enhanced when autophagy is activated and is primarily prevented when autophagy is inhibited. This mechanism of aggresome clearance is not unique to peripheral glia, because L fibroblasts were also capable of removing aggresomes. Our results provide evidence for the involvement of the proteasome pathway in TrJ neuropathy and for the role of autophagy in the clearance of aggresomes.




Animals; Autophagy/physiology; Cells, Cultured; Cysteine Endopeptidases/metabolism; Fibroblasts/cytology; Fibroblasts/metabolism; HSC70 Heat-Shock Proteins; HSP70 Heat-Shock Proteins/metabolism; In Vitro Techniques; Lysosomes/metabolism; Macromolecular Substances; Mice; Mice, Knockout; Mice, Neurologic Mutants; Molecular Chaperones/metabolism; Multienzyme Complexes/metabolism; Myelin Proteins/deficiency; Myelin Proteins/genetics; Myelin Proteins/metabolism; Organelles/metabolism; Proteasome Endopeptidase Complex; Rats; Schwann Cells/cytology; Schwann Cells/metabolism; Sciatic Nerve/metabolism; Sciatic Nerve/ultrastructure; Ubiquitin/metabolism