Inhibition of the ubiquitin-proteasome system in Alzheimer's disease

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2000
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Abstract
Alzheimer's disease is the most common cause of dementia in the elderly. Although several genetic defects have been identified in patients with a family history of this disease, the majority of cases involve individuals with no known genetic predisposition. A mutant form of ubiquitin, termed Ub(+1), has been selectively observed in the brains of Alzheimer's patients, including those with nonfamilial Alzheimer's disease, but it has been unclear why Ub(+1) expression should be deleterious. Here we show that Ub(+1) is an efficient substrate for polyubiquitination in vitro and in transfected human cells. The resulting polyubiquitin chains are refractory to disassembly by deubiquitinating enzymes and potently inhibit the degradation of a polyubiquitinated substrate by purified 26S proteasomes. Thus, expression of Ub(+1) in aging brain could result in dominant inhibition of the Ub-proteasome system, leading to neuropathologic consequences.
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Authors Y. A. Lam,C. M. Pickart,A. Alban,M. Landon,C. Jamieson,R. Ramage,R. J. Mayer,Robert Layfield;Y. A. Lam;C. M. Pickart;A. Alban;M. Landon;C. Jamieson;R. Ramage;R. J. Mayer;Robert Layfield;
Journal proceedings of the national academy of sciences
Year 2000
DOI
10.1073/pnas.170173897
URL
https://sciprofiles.com/publication/view/4cf18a25c157213c1664eff213a82c47
Keywords
proteasome alzheimer's disease brains polyubiquitinated substrate polyubiquitination inhibit

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