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

Abstract

Free radical-mediated damage to macromolecules and the resulting oxidative modification of different cellular components are a common feature of aging, and this process becomes much more pronounced in age-associated pathologies, including Alzheimer disease (AD). In particular, proteins are particularly sensitive to oxidative stress-induced damage and these irreversible modifications lead to the alteration of protein structure and function. In order to maintain cell homeostasis, these oxidized/damaged proteins have to be removed in order to prevent their toxic accumulation. It is generally accepted that the age-related accumulation of "aberrant" proteins results from both the increased occurrence of damage and the decreased efficiency of degradative systems. One of the most important cellular proteolytic systems responsible for the removal of oxidized proteins in the cytosol and in the nucleus is the proteasomal system. Several studies have demonstrated the impairment of the proteasome in AD thus suggesting a direct link between accumulation of oxidized/misfolded proteins and reduction of this clearance system. In this review we discuss the impairment of the proteasome system as a consequence of oxidative stress and how this contributes to AD neuropathology. Further, we focus the attention on the oxidative modifications of a key component of the ubiquitin-proteasome pathway, UCHL1, which lead to the impairment of its activity.

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.