title: Review: unchained maladie - a reassessment of the role of Ubb(+1) -capped polyubiquitin chains in Alzheimer's disease.
abstract: Molecular misreading allows the formation of mutant proteins in the absence of gene mutations. A mechanism has been proposed by which a frameshift mutant of the ubiquitin protein, Ubb(+1) , which accumulates in an age-dependent manner as a result of molecular misreading, contributes to neuropathology in Alzheimer's disease (Lam et al. 2000). Specifically, in the Ubb(+1) -mediated proteasome inhibition hypothesis Ubb(+1) 'caps' unanchored (that is, nonsubstrate linked) polyubiquitin chains, which then act as dominant inhibitors of the 26S proteasome. A review of subsequent literature indicates that this original hypothesis is broadly supported, and offers new insights into the mechanisms accounting for the age-dependent accumulation of Ubb(+1) , and how Ubb(+1) -mediated proteasome inhibition may contribute to Alzheimer's disease. Further, recent studies have highlighted a physiological role for free endogenous unanchored polyubiquitin chains in the direct activation of certain protein kinases. This raises the possibility that Ubb(+1) -capped unanchored polyubiquitin chains could also exert harmful effects through the aberrant activation of tau or other ubiquitin-dependent kinases, neuronal NF-κB activity or NF-κB-mediated neuroinflammatory processes.
authors.affiliation: School of Biomedical Sciences, University of Nottingham, UK.
authors.forename: L
authors.initials: L
authors.lastname: Chadwick
authors.forename: L
authors.initials: L
authors.lastname: Gentle
authors.forename: J
authors.initials: J
authors.lastname: Strachan
authors.forename: R
authors.initials: R
authors.lastname: Layfield
mesh_terms: D000375:Aging / Q000235:genetics; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D016368:Frameshift Mutation / Q000235:genetics*; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D025821:Polyubiquitin / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D051381:Rats; D025801:Ubiquitin / Q000235:genetics* / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016328:NF-kappa B; C479419:UBB protein, human; D025801:Ubiquitin; D016875:tau Proteins; D025821:Polyubiquitin; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease