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Alzheimer's associated variant ubiquitin causes inhibition of the 26S proteasome and chaperone expression
Author(s) -
Hope Andrew D.,
De Silva Rohan,
Fischer David F.,
Hol Elly M.,
Van Leeuwen Fred W.,
Lees Andrew J.
Publication year - 2003
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2003.01844.x
Subject(s) - proteasome , chaperone (clinical) , ubiquitin , microbiology and biotechnology , heat shock protein , chemistry , lactacystin , hsp90 , biology , proteasome inhibitor , biochemistry , medicine , gene , pathology
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.