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- Title
Alzheimer's associated variant ubiquitin causes inhibition of the 26S proteasome and chaperone expression.
- Authors
Hope, Andrew D; de Silva, Rohan; Fischer, David F; Hol, Elly M; van Leeuwen, Fred W; Lees, Andrew J
- Abstract
Intracellular protein inclusions in Alzheimer's disease and progressive supranuclear palsy contain UBB+1, a variant ubiquitin. UBB+1 is able block the 26S proteasome in cell lines. Proteasome inhibition by drug action has previously been shown to induce a heat-shock response and render protection against stress. We investigated UBB+1 by developing a stable, conditional expression model in SH-SY5Y human neuroblastoma cells. Induction of UBB+1 expression caused proteasome inhibition as was confirmed by reduced ability to process misfolded canavanyl proteins, accumulation of GFPu, a proteasome substrate, and reduced cleavage of a fluorogenic substrate. We show that expression of UBB+1 induces expression of heat-shock proteins. This priming of the chaperone system in these cells promotes a subsequent resistance to tert-butyl hydroperoxide-mediated oxidative stress. We conclude that although UBB+1-expressing cells have a compromised ubiquitin-proteasome system, they are protected against oxidative stress conditions.
- Publication
Journal of neurochemistry, 2003, Vol 86, Issue 2, p394
- ISSN
0022-3042
- Publication type
Journal Article
- DOI
10.1046/j.1471-4159.2003.01844.x