Ubiquitin-Proteasome System and Proteasome Inhibition: New Strategies in Stroke Therapy

Abstract

Background and Purpose-Proteasomes are large multicatalytic proteinase complexes that are found in the cytosol and in the nucleus of eukaryotic cells with a central role in cellular protein turnover. The ubiquitin-proteasome system (UPS) has a central role in the selective degradation of intracellular proteins. Among the key proteins whose levels are modulated by the proteasome are those involved in the control of inflammatory processes, cell cycle regulation, and gene expression. There are now overwhelming data suggesting that the UPS contributes to cerebral ischemic injury. Summary of Review-Proteasome inhibition is a potential treatment option for stroke. Thus far, proof of principle has been obtained from studies in several animal models of cerebral ischemia. Treatment with proteasome inhibitors reduces effectively neuronal and astrocytic degeneration, cortical infarct volume, infarct neutrophil infiltration, and NF-B immunoreactivity with an extension of the neuroprotective effect at least 6 hours after ischemic insult. However, it is clear that the UPS represents a central pathway for the processing and metabolism of multiple proteins with critical roles in cellular function. To avoid eliciting significant side effects associated with complete inhibition of the proteasome and the possible immunosuppressive effects from persistent suppression of NF-B activation, it is critical that we understand how to partially and temporally attenuate proteasome function to elicit the desired therapeutic effect before any large-scale use in humans. Conclusion-This review highlights the most recent advances in our knowledge on UPS, as well as the early experience of using proteasome inhibition strategies to treat acute stroke.

Proteasome Inhibition Induces Glutathione Synthesis and Protects Cells from Oxidative Stress

“…It is known that nuclear factor-B (NF-B) translocates to the nucleus, where it binds to specific promoter sequences, initiating the transcription of NF-Bdependent genes, many of which are mediators of inflammatory response (25). In dopaminergic neurons of patients with PD, nuclear translocation of NF-B is enhanced (26), and proteasome inhibition suppresses the activities of NF-B by stabilizing the inhibitory protein IB (27). Moreover, we demonstrated that proteasome inhibition accelerated the appearance of ␣-synucleinpositive inclusion bodies and provided neuroprotection (28,29).…”

Glutamine attenuates inflammation and NF-κB activation via Cullin-1 deneddylation

“…Following activation by a wide array of mediators, including cytokines, bacterial toxins, or oxidative stress, the signal transduction cascade is initiated, which causes the phosphorylation of IkBα on Ser32 and -36 by IKK complex [19]. Phosphorylation of IkBα is followed by ubiquitination via the E3 ligase SCFβ TRCP and is targeted for proteasomal degradation by the 26S proteasome [20].…”

Morphine Induces Ubiquitin-Proteasome Activity and Glutamate Transporter Degradation

“…In addition, activation of UPS has been shown to regulate the PSD-95 degradation and ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor surface expression (12), suggesting a possible relationship between UPS and glutamatergic activities. Ubiquitination is a process involving three enzymes: E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3 (ubiquitin ligase) (13,14). Interactions between an E3 ligase and its target molecule are considered a key step in determining the selectivity of UPS for a target molecule and its subsequent proteasomal degradation, a process that is subject to intracellular modulation by various upstream regulators (14).…”