Autophagy is activated by proteasomal inhibition and involved in aggresome clearance in cultured astrocytes.
A common pathway underlying a variety of neurodegenerative disorders is the aggregation and deposition of misfolded proteins. Proteasomal inhibition has been demonstrated to promote the formation of intracellular inclusions. We have shown before that astrocytes respond to the treatment with the proteasome inhibitor MG-132 by aggresome formation and cytoskeletal disturbances, but unlike oligodendrocytes do not die by apoptotic cell death and have the capability to recover. This study was undertaken to elucidate if the autophagy-lysosomal pathway participates in the efficient recovery process in astrocytes and is modulated under conditions of proteasomal inhibition. The data show that the autophagic pathway was stimulated during a 24-h treatment with the proteasome inhibitor MG-132 in a time and concentration-dependent manner. It remained at an elevated level throughout a 24-h recovery period in the absence of MG-132 and participates in the aggregate clearing process. In the presence of the specific inhibitor of macroautophagy, 3-methyladenine, cell viability was impaired, aggregates were not as efficiently removed and HSP25, αB-crystallin and ubiquitinated proteins remained in the insoluble protein fraction. LC3-II positive puncta, indicative of autophagosomes, were formed abundantly in the cells after proteasome inhibition and were seen in close association with the aggregates. Hence, the ability of astrocytes to upregulate autophagic degradation might contribute to their resistance against proteasomal stress situations and act as a compensatory mechanism when the proteasome is impaired.
Jänen
Sven B
SB
Department of Biology, Molecular Neurobiology, University of Oldenburg, Oldenburg, Germany.
Chaachouay
Hassan
H
Richter-Landsberg
Christiane
C
D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D002449:Cell Aggregation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003599:Cytoskeleton / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D002479:Inclusion Bodies / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D007976:Leupeptins / Q000494:pharmacology; D019636:Neurodegenerative Diseases / Q000201:enzymology / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism; D061988:Proteasome Inhibitors; D051381:Rats; D017208:Rats, Wistar
D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde