Review: Unchained maladie - a reassessment of the role of Ubb+1-capped polyubiquitin chains in Alzheimer's disease.

L. Chadwick, L. Gentle, J. Strachan and R. Layfield (2012) Neuropathology and Applied Neurobiology 38, 118-131 Unchained maladie - a reassessment of the role of Ubb⁺¹-capped polyubiquitin chains in Alzheimer's disease 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. [ABSTRACT FROM AUTHOR]