Activation of autophagy by rapamycin does not protect oligodendrocytes against protein aggregate formation and cell death induced by proteasomal inhibition.

Pathological protein inclusions containing the microtubule-associated protein tau, ubiquitin, and a variety of heat shock proteins, originating in oligodendrocytes, are consistent features observed in a number of neurodegenerative diseases. Defects in the proteolytic degradation systems have been associated with protein aggregate formation. The ubiquitin proteasome system (UPS) and autophagy are critically involved in the maintenance of cellular homeostasis and their activities need to be carefully balanced. A genuine crosstalk exists between the UPS and the autophagosomal system, and when the UPS is impaired, autophagy might act as a compensatory mechanism. Autophagy represents a lysosomal degradation system for degrading long-lived proteins and organelles, including damaged mitochondria. As we have shown before, proteasomal impairment by the reversible proteasomal inhibitor MG-132 (carbobenzoxy-L-leucyl-L-leucyl-L-leucinal) in oligodendrocytes leads to protein aggregate formation and apoptotic cell death, caused by activation of caspases and the mitochondrial pathway. The present study was undertaken to elucidate whether upregulation of the autophagic pathway by rapamycin can protect oligodendrocytes and ameliorate the consequences of MG-132-induced protein aggregate formation. The data show that rapamycin attenuated the formation of dense protein aggregates, but did not enhance the survival capability of oligodendrocytes after proteasomal inhibition. After activation of the autophagic pathway in combination with proteasomal inhibition, caspase 3 activation and poly(ADP-ribose) polymerase-1 cleavage were even more pronounced than after proteasomal inhibition alone. Furthermore, rapamycin augmented MG-132-induced activation of extracellular signal-regulated kinases 1 and 2, which are involved in the regulation of cell death and survival. In summary, depending on the cellular context and system, rapamycin may promote cell survival or, under other conditions in concert with apoptosis, may augment cell death, which seems to be the case in oligodendrocytes. Its therapeutic use for neurodegenerative disorders is most likely limited, since long-term administration may impair neuronal survival and specifically damage the myelin forming cells of the CNS.