The Small Heat Shock Protein HSP25/27 (HspB1) Is Abundant in Cultured Astrocytes and Associated with Astrocytic Pathology in Progressive Supranuclear Palsy and Corticobasal Degeneration.

Filamentous tau-positive protein inclusions in neurons and glia are prominent features of a number of neurodegenerative disorders termed tauopathies. These inclusions are further characterized by the presence of heat shock proteins (HSPs). The group of small HSPs, namely, HSP27 and alphaB-crystallin, interact with the cytoskeleton, bind to nonnative proteins, and prevent their aggregation after stress. To further investigate their contribution to neurodegenerative diseases, we have analyzed the association of HSP27 with pathological lesions of tauopathies. Microarray and immunoblot analysis revealed that HSP27 is enhanced at the mRNA and protein levels in affected brains, and that it is associated with astrocytic pathology. The upregulation of HSP27 in tauopathies with gial pathology implies distinct mechanisms for glial and neuronal cells. This was sustained by cell culture studies, demonstrating that the small HSPs are specifically and prominently expressed in unstressed astrocytes and not in neurons and in neurons remained at a rather low level even after stress situations.

Proteasome inhibition by MG-132 induces apoptotic cell death and mitochondrial dysfunction in cultured rat brain oligodendrocytes but not in astrocytes.

Proteasomal dysfunction has been implicated in neurodegenerative disorders and during aging processes. In frontotemporal dementias, corticobasal degeneration, and progressive supranuclear palsy, oligodendrocytes are specifically damaged. Application of proteasomal inhibitors to cultured oligodendrocytes is associated with apoptotic cell death. The present study was undertaken to investigate the death pathway activated in oligodendrocytes by proteasomal inhibition. Our data show that the proteasomal inhibitor MG-132 causes oxidative stress, as indicated by the upregulation of the small heat shock protein heme oxygenase-1 (HO-1) and the appearance of oxidized proteins. Activation of the mitochondrial pathway was involved in the apoptotic process. Mitochondrial membrane potential was disturbed, and cytochrome c was released from the mitochondria. Concomitantly, death-related caspases 3 and 9 were activated and poly(ADP-ribose)-polymerase cleavage occurred. MG-132-induced cell death, DNA-fragmentation, and caspase activation could be prevented by the broad caspase inhibitor zVAD-fmk. In contrast to oligodendrocytes, cultured astrocytes showed resistance to the treatment with proteasomal inhibitors and did not reveal cytotoxic responses. This was also observed in astrocytes differentiated in the presence of dibutyryl cyclic AMP. Hence, individual cells respond differently to proteasomal inhibition and the therapeutic use of proteasomal inhibitors, e.g. for the treatment of cancer or inflammatory diseases, needs to be carefully evaluated.