Alzheimer's associated variant ubiquitin causes inhibition of the 26S proteasome and chaperone expression
Article first published online: 4 FEB 2004
Journal of Neurochemistry
Volume 86, Issue 2, pages 394–404, July 2003
How to Cite
Hope, A. D., De Silva, R., Fischer, D. F., Hol, E. M., Van Leeuwen, F. W. and Lees, A. J. (2003), Alzheimer's associated variant ubiquitin causes inhibition of the 26S proteasome and chaperone expression. Journal of Neurochemistry, 86: 394–404. doi: 10.1046/j.1471-4159.2003.01844.x
- Issue published online: 4 FEB 2004
- Article first published online: 4 FEB 2004
- Received March 14, 2003; revised manuscript received April 4, 2003; accepted April 4, 2003.
- Alzheimer's disease;
- heat-shock proteins;
- oxidative stress;
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.