Relationship between the ubiquitin-dependent pathway and apoptosis in different cells of the central nervous system: Effect of thyroid hormones

We have recently shown that sustained neonatal hyperthyroidism in the rat a ctivates apoptosis of oligodendroglial cells (OLGc) and that inhibition of the proteasome-ubiquitin (Ub) pathway by lactacystin produces increased apo ptosis in cerebellar granule cells (CGC). In the present study we have anal yzed the relationship between the activation of the Ub-dependent pathway, t he expression of the Ub genes and programmed cell death in neurons of the r at cerebellum and cerebral cortex and in OLGc. This study was carried out i n normal animals, in rats submitted to sustained neonatal hyperthyroidism a nd in cell cultures treated with an excess of thyroid hormones. In neurons of the cerebral cortex, thyroid hormone produces an increase of Ub-protein conjugates, an enhancement in the expression of the Ub genes and an increas e in apoptosis, while the opposite results are obtained in CGC. These resul ts indicate that in neurons, the changes in the cell death program produced by thyroid hormone run in parallel with those occurring in the Uh-dependen t pathway. In OLGc, thyroid hormone increases apoptosis but does not produc e changes in the Ub pathway. Preliminary studies indicate that in coinciden ce with what occurs in optic nerves, the sciatic nerves both in controls an d in hyperthyroid animals are unable to form Ub-protein conjugates. These r esults indicate that in cells of the CNS such as neurons, in which the Ub-d ependent pathway is actively expressed, it appears to be closely correlated with apoptosis.