It Is All about (U)biquitin: Role of Altered Ubiquitin-Proteasome System and UCHL1 in Alzheimer Disease

Figure 1

Oxidative stress impairs the functionality of the UPS in AD. Under physiological conditions the ubiquitin-proteasome system (UPS) mediates the clearance of misfolded proteins in order to prevent their toxic accumulation. Indeed, a target protein undergoes multiple cycles during which it is conjugated with one or more ubiquitin groups leading to mono- or polyubiquitinylated substrates (S). In particular, in the first step of this cycle, ubiquitin activating enzyme (E1) forms a thioester bond with ubiquitin and this reaction requires ATP as driving force. Subsequently, the ubiquitin group is transferred to ubiquitin-conjugating enzyme (E2), which works as a scaffold protein favoring the interaction between ubiquitin ligase (E3) and the target substrate, aimed at allowing the ligase to transfer the ubiquitin group from E2 to the substrate. After a number of cycles promoting the polyubiquitinylation of the substrate, this latter is driven to the proteasome for its degradation. Polyubiquitinylated substrates also can be targets of the activity of the ubiquitin carboxyterminal hydrolase L1 (UCLH1), which is highly expressed in neurons and hydrolyses small adducts of ubiquitin to generate the ubiquitin monomer. During the progression of Alzheimer disease (AD), increased amyloid-beta (Aβ) production and accumulation favor the augmentation of oxidative stress levels, which leads to protein oxidative modifications (Ox). Because oxidized proteins are neurotoxic, they would be eliminated through the UPS, but this does not seem to be the case in AD. Indeed, both Aβ and oxidative stress would promote the impairment of the UPS and the consequent accumulation of polyubiquitinylated proteins, which are visible as aggregates in AD brain. Arrows, promotion; lines, inhibition. Black, physiological conditions; red, pathological conditions.