Necrosis of Schwann cells during tellurium-induced primary demyelination: DNA fragmentation, reorganization of splicing machinery, and formation of intranuclear rods of actin

We present a cytological, immunocytochemical, and biochemical study of the cell death of mature myelinating Schwann cells (SCs) in the primary demyelinating neuropathy induced by tellurium (Te). Weaned rats were fed a diet containing 1.1% elemental Te. The animals were killed daily within the first week of Te diet. After 4 to 6 days of Te treatment some SCs underwent degeneration and necrosis, By electron microscopy analysis, degenerating SCs showed chromatin condensation, detachment from the nuclear envelope of condensed chromatin clumps, aggregation of interchromatin granule clusters, formation of intranuclear bundles of microfilaments, and cytoplasmic vesiculation. By confocal laser fluorescence microscopy, chromatin regions were stained with the TUNEL method for in situ labeling of DNA fragmentation and exhibited a progressive reduction of histone signal. In addition, splicing small nuclear ribonucleoprotein (snRNP) factors were redistributed in a few large nuclear domains and bright foci of intranuclear actin were observed. DNA electrophoresis revealed a smear pattern of DNA fragmentation in sciatic nerve samples from Te-treated animals. Upon Te treatment, no degradation of the caspase substrates poly (ADP-ribose) polymerase and lamin B was detected by Western blots or immunocytochemistry, respectively. The peculiar structural rearrangement of the transcription and splicing machinery as well as the vesicular degeneration of the cytoplasm in degenerating SCs support an autophagic cell death of the necrotic type. Unlike the apoptosis of pre-remyelinating SCs (11), this caspase independent cell death of necrotic type involves mature pre-demyelinating SCs and eliminates SCs injured by the neurotoxic effect of Te.