Does an inhibition of the ubiquitin/26S proteasome pathway of protein degradation underlie the pathogenesis of non-familial Alzheimer's disease?

Abstract

The ubiquitin/26S proteasome pathway catalyses the degradation of key regulatory proteins, as well as of misfolded or damaged polypeptides. Central to this pathway is the posttranslational covalent conjugation of ubiquitin to other eukaryotic target proteins, which acts as a signal for target protein degradation by the 26S proteasome proteolytic complex. Here, I propose a mechanism by which the expression of a frameshift ubiquitin mutant (termed 'ubiquitin(+1)'), which arises in the ageing human brain as a result of a process known as 'molecular misreading', could lead to a progressive age-dependent inhibition of the 26S proteasome. Further, I propose that such an inhibition contributes directly to Alzheimer's disease pathogenesis.