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The Journal of Neuroscience, June 23, 2004, 24(25):5748-5757; doi:10.1523/JNEUROSCI.1307-04.2004

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Neurobiology of Disease
Proteolytic Stress Causes Heat Shock Protein Induction, Tau Ubiquitination, and the Recruitment of Ubiquitin to Tau-Positive Aggregates in Oligodendrocytes in Culture

Olaf Goldbaum and Christiane Richter-Landsberg

Department of Biology, Molecular Neurobiology, University of Oldenburg, D-26111 Oldenburg, Germany

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 B-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, B-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 B-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 B-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.

Key words: B-crystallin; tau; ubiquitin; cytoskeleton; glial inclusions; proteasome; apoptosis

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Received Dec 11, 2003; revised May 10, 2004; accepted May 10, 2004.

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