Proteolytic stress causes heat shock protein induction, tau ubiquitination, and the recruitment of ubiquitin to tau-positive aggregates in oligodendrocytes in culture.
Molecular chaperones and the ubiquitin-proteasome system are participants in the defense against unfolded proteins and provide an effective protein quality control system that is essential for cellular functions and survival. Ubiquitinated tau-positive inclusion bodies containing the small heat shock protein alphaB-crystallin in oligodendrocytes are consistent features of a variety of neurodegenerative diseases, and defects in the proteasome system might contribute to the aggregation process. Oligodendrocytes, the myelin-forming cells of the CNS, are specifically sensitive to stress situations. Here we can show that in cultured rat brain oligodendrocytes proteasomal inhibition by MG-132 or lactacystin caused apoptotic cell death and the induction of heat shock proteins in a time- and concentration-dependent manner. Specifically, alphaB-crystallin was upregulated, and ubiquitinated proteins accumulated. After incubation with MG-132 the tau was dephosphorylated, which enhanced its microtubule-binding capacity. Proteasomal inhibition led to ubiquitination of tau and its association with alphaB-crystallin and to the occurrence of thioflavine S-positive aggregates in the oligodendroglial cytoplasm. These aggregates were positive for tau and also contained ubiquitin and alphaB-crystallin; hence they resembled the glial cytoplasmic inclusions observed in white matter disease and frontotemporal dementias with parkinsonism linked to chromosome 17 (FTDP-17). In summary, the data underscore the specific sensitivity of oligodendrocytes to stress situations and point to a causal relationship of proteasomal impairment and inclusion body formation.
Goldbaum
Olaf
O
Department of Biology, Molecular Neurobiology, University of Oldenburg, D-26111 Oldenburg, Germany.
Richter-Landsberg
Christiane
C
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000166:cytology / Q000378:metabolism; D002478:Cells, Cultured; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis; D006360:Heat-Shock Proteins / Q000096:biosynthesis* / Q000235:genetics; D002479:Inclusion Bodies / Q000378:metabolism; D007976:Leupeptins / Q000494:pharmacology; D008870:Microtubules / Q000378:metabolism; D009836:Oligodendroglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress; D010766:Phosphorylation; D061988:Proteasome Inhibitors; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D025801:Ubiquitin / Q000378:metabolism*; D038203:alpha-Crystallin B Chain / Q000096:biosynthesis; D016875:tau Proteins / Q000378:metabolism*
D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D007976:Leupeptins; D061988:Proteasome Inhibitors; D012333:RNA, Messenger; D025801:Ubiquitin; D038203:alpha-Crystallin B Chain; D016875:tau Proteins; C067713:lactacystin; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D000111:Acetylcysteine