Activation of the autophagy, c-FOS and ubiquitin expression, and nucleolaralterations in Schwann cells precede demyelination in tellurium-induced neuropathy

We have used an experimental model of tellurium (Te)-induced demyelinating neuropathy in the rat to study cellular mechanisms involved in the early re sponse of myelinating Schwann cells (SCs) to injury, prior to demyelination . Starting at postnatal day 21, weaned rats were fed a diet containing 1.1% elemental Te. The animals were killed daily within the Ist week of Te diet and the sciatic nerves were processed for the ultrastructural and immunocy tochemical studies. Immunohistochemistry revealed that Te induces an increa sed nuclear expression of c-Fos in SCs. By electron microscopy analysis, th e early cytoplasmic alteration was a dramatic disorganization of the rough endoplasmic reticulum (ER) with cisternal dilations and redistribution and loss of membrane-bound ribosomes. This was followed by a prominent activati on of the macroautophagy in SCs. This process involved the formation of aut ophagosomes containing well-preserved cell organelles, autolysosomes with c ellular remnants in various phases of degeneration and lysosomes. Te treatm ent also induced the expression of free ubiquitin in the perikaryal region of the SC cytoplasm. Immunogold electron microscopy showed the subcellular distribution of ubiquitin in the cytosol, around of dilated ER cisterns and in the matrix of autolysosomes and residual bodies. At the nucleolar level , fibrillarin immunofluorescence revealed nucleolar segregation in SCs expo sed to Te. The ultrastructural study confirmed the segregation of the nucle olar components with a peripheral distribution of the dense fibrillar compo nent. These results support the hypothesis that the depletion of cholestero l induced by Te treatment triggers a stress response in myelinating SCs med iated by immediate early genes of the fos family. The cellular response inc ludes a severe disruption of the protein synthesis machinery, namely the ro ugh ER and nucleolus, with the subsequent activation of both ubiquitin and autophagic pathways of proteins and cell organelle degradation. This cytopl asmic remodeling may represent a cytoprotective mechanism in the response o f SCs to a neurotoxic stress. Furthermore, it must be a prerequisite for th e induction of phenotypic changes and cell repair mechanisms in SCs.