Alzheimer's associated variant ubiquitin causes inhibition of the 26S proteasome and chaperone expression

作者：Hope AD^*; de Silva R; Fischer DF; Hol EM; van Leeuwen FW; Lees AJ

来源：Journal of Neurochemistry, 2003, 86(2): 394-404.

DOI：10.1046/j.1471-4159.2003.01844.x

• Alzheimer's disease
• heat-shock proteins
• oxidative stress
• ubiquitin
• UBB+1

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 GFP(u) , 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.

• 出版日期2003-7