a Abbreviations: hERG, human ether-a-go-go gene related product; TdP, torsades de pointes; minK, minimal potassium channel; KvLQT1, potassium voltage-gated channel subfamily KQT member 1; Kir2, inward rectifier potassium channel 2; IKr, potassium voltage-gated channel ether-a-go-go protein; IKs, slow voltage producing potassium channel β subunit; KcsA, Streptomyces liVidans potassium channel; MthK, Methanobacterium thermoautotrophicum potassium channel; KvAP, Aeropyrum pernix voltagedependent potassium channel; APD, action potential duration; MAP, monophasic action potential; GRIND, grid independent descriptors; MLR, multiple linear regression; DSM, discrete structural modifications; ZI, zwitterion.

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.