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

Alzheimer's disease is the most common cause of dementia in the elderly. Al though several genetic defects have been identified in patients with a fami ly 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, inclu ding those with nonfamilial Alzheimer's disease, but it has been unclear wh y Ub(+1) expression should be deleterious. Here we show that Ub(+1) is an e fficient 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 polyubi quitinated substrate by purified 26S proteasomes. Thus, expression of Ub(+1 ) in aging brain could result in dominant inhibition of the Ub-proteasome s ystem, leading to neuropathologic consequences.