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

Hope, AD; de Silva, R; Fischer, DF; Hol, EM; van Leeuwen, FW; Lees, AJ; (2003) Alzheimer's associated variant ubiquitin causes inhibition of the 26S proteasome and chaperone expression. J NEUROCHEM , 86 (2) 394 - 404. 10.1046/j.1471-4159.2003.01844.x.

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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 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.

Type: Article
Title: Alzheimer's associated variant ubiquitin causes inhibition of the 26S proteasome and chaperone expression
DOI: 10.1046/j.1471-4159.2003.01844.x
Keywords: Alzheimer's disease, heat-shock proteins, oxidative stress, ubiquitin, UBB+1, MOLECULAR CHAPERONES, MUTANT UBIQUITIN, SACCHAROMYCES-CEREVISIAE, PARKINSONS-DISEASE, NEUROFIBRILLARY TANGLES, DEPENDENT DEGRADATION, AGGRESOME FORMATION, MISFOLDED PROTEINS, FRAMESHIFT MUTANT, OXIDIZED PROTEINS
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences
URI: http://discovery.ucl.ac.uk/id/eprint/116666
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