Inhibition of the ubiquitin-proteasome system in Alzheimer's disease.
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.
Lam
Y A
YA
Department of Biochemistry, School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA.
Pickart
C M
CM
Alban
A
A
Landon
M
M
Jamieson
C
C
Ramage
R
R
Mayer
R J
RJ
Layfield
R
R
D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D000595:Amino Acid Sequence; D002460:Cell Line; D005786:Gene Expression Regulation; D006801:Humans; D007668:Kidney; D007700:Kinetics; D008969:Molecular Sequence Data; D010447:Peptide Hydrolases / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection; D014452:Ubiquitins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
D011994:Recombinant Proteins; D014452:Ubiquitins; D010447:Peptide Hydrolases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease