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

Abstract

We have used an experimental model of tellurium (Te)-induced demyelinating neuropathy in the rat to study cellular mechanisms involved in the early response 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 1st week of Te diet and the sciatic nerves were processed for the ultrastructural and immunocytochemical studies. Immunohistochemistry revealed that Te induces an increased nuclear expression of c-Fos in SCs. By electron microscopy analysis, the 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 activation of the macroautophagy in SCs. This process involved the formation of autophagosomes containing well-preserved cell organelles, autolysosomes with cellular remnants in various phases of degeneration and lysosomes. Te treatment 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 exposed to Te. The ultrastructural study confirmed the segregation of the nucleolar components with a peripheral distribution of the dense fibrillar component. These results support the hypothesis that the depletion of cholesterol induced by Te treatment triggers a stress response in myelinating SCs mediated by immediate early genes of the fos family. The cellular response includes a severe disruption of the protein synthesis machinery, namely the rough ER and nucleolus, with the subsequent activation of both ubiquitin and autophagic pathways of proteins and cell organelle degradation. This cytoplasmic remodeling may represent a cytoprotective mechanism in the response of SCs to a neurotoxic stress. Furthermore, it must be a prerequisite for the induction of phenotypic changes and cell repair mechanisms in SCs.

Formation of intranuclear crystalloids and proliferation of the smooth endoplasmic reticulum in schwann cells induced by tellurium treatment: Association with overexpression of HMG CoA reductase and HMG CoA synthase mRNA

“…This facilitates the study of cellular events that precede demyelination and proliferation of SC. As we reported previously (Calle et al, 1999), the most prominent initial alteration in myelinating SC was the disorganization of the rough ER and subsequent activation of macroautophagy within 2 to 4 days of Te treatment (Fig. 3A) After this autophagic phase, most of large myelinating SC exposed to Te underwent a reactive response with cellular hypertrophy that started before the demyelination phase and extended to the proliferative phase (Figs.…”

“…After 2-4 days of Te treatment, most myelinating SC belonging to large nerve fibers were in the autophagic phase, as previously reported (Calle et al, 1999). The SC showed a dramatic disorganization of the cytoplasm due to the accumulation of autophagic vacuoles, while the normal structural organization of the cell nucleus was preserved (Fig.…”

Diphenyl ditelluride induces neurotoxicity and impairment of developmental behavioral in rat pups

“…It is clearly demonstrated in Figure 6 that there is no major decrease in myelin content but rather stagnation with any new myelin being formed. The fact that tellurium blocks cholesterol synthesis and causes down-regulation of myelin gene expression [31][32][33][34] could help to explain the stagnation of myelin synthesis seen in rat pups exposed to (PhTe) 2 . The unusual sensitivity of the enzyme to tellurium is due to reaction with sulfhydryls and the binding to the vicinal cysteines on squalene monooxygenase.…”

PICT-1 triggers a pro-death autophagy through inhibiting rRNA transcription and AKT/mTOR/p70S6K signaling pathway

“…Several recent studies suggest that the nucleolus has a close relationship to autophagic processes. Firstly, a number of cell stressors have been found to induce both nucleolar dysfunction and autophagy [20]. Secondly, autophagy-related signalling molecules can also regulate ribosomal RNA (rRNA) transcription and ribosomal biogenesis [21,22].…”