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

Abstract

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 concentrationdependent 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.

Cockayne syndrome exhibits dysregulation of p21 and other gene products that may be independent of transcription-coupled repair

“…We have validated over-expression of Hsp90 and Dp-1 by western analysis, and results are shown for Hsp90 (Fig 7). The observation of an increased level of a heat shock protein is consistent with recent studies showing that dysregulation of the ubiquitylation and proteasome systems results in induction of several heat shock proteins and accumulation of tau proteins in oligodendrocytes, precursors for myelin synthesizing cells (Goldbaum and Richter-Landsberg, 2004). The increase in CAF-1 may be related to the slow recovery of DNA synthesis after DNA damage to CS cells because this protein interacts with PCNA (Cleaver, 1982).…”

Tau-induced neurodegeneration: mechanisms and targets

“…The phosphorylation state of tau has been implicated in the degeneration of neurons [101] and linked to mitochondrial dysfunction [102] . Tau has also been shown to be ubiquitinated and to be involved in the cellular distribution of mitochondria in mouse neurons [103,104] .…”

“…The phosphorylation state of tau has been implicated in the degeneration of neurons [101] and linked to mitochondrial dysfunction [102] . Tau has also been shown to be ubiquitinated and to be involved in the cellular distribution of mitochondria in mouse neurons [103,104] .In 2009, a transgenic mouse strain that mimics both Aβ plaque formation and tau tangles was analyzed and it was found that both the plaques and the tangles affected the OXPHOS of the mitochondria [105] . In a more recent work, it has been shown that reduction of the expression of soluble tau is important for the proper distribution of mitochondria in the neurons of rTg4510 mice [104] .…”

Protein aggregate formation in oligodendrocytes: tau and the cytoskeleton at the intersection of neuroprotection and neurodegeneration

“…HSPs are upregulated as a first line of defense against the accumulation of misfolded proteins, keep unfolded proteins in a competent state to be refolded, and may prevent cell death und maintain the cytoskeleton (Richter-Landsberg and . Proteasomal inhibition leads to HSP induction (Goldbaum and Richter-Landsberg, 2004), and the autophagosomal system can act as a compensatory mechanism when the UPS is impaired (Pandey et al, 2007;Jaenen et al, 2010). Several proteins have been identified, which link the UPS with the autophagic degradation system, including the receptors for ubiquitinated protein aggregates p62/ sequestosome 1 and HDAC6 (histone deacetylase 6).…”