Disruption of the Ubiquitin-Proteasome System and Elevated Endoplasmic Reticulum Stress in Epilepsy

Abstract

The epilepsies are a broad group of conditions characterized by repeated seizures, and together are one of the most common neurological disorders. Additionally, epilepsy is comorbid with many neurological disorders, including lysosomal storage diseases, syndromic intellectual disability, and autism spectrum disorder. Despite the prevalence, treatments are still unsatisfactory: approximately 30% of epileptic patients do not adequately respond to existing therapeutics, which primarily target ion channels. Therefore, new therapeutic approaches are needed. Disturbed proteostasis is an emerging mechanism in epilepsy, with profound effects on neuronal health and function. Proteostasis, the dynamic balance of protein synthesis and degradation, can be directly disrupted by epilepsy-associated mutations in various components of the ubiquitin-proteasome system (UPS), or impairments can be secondary to seizure activity or misfolded proteins. Endoplasmic reticulum (ER) stress can arise from failed proteostasis and result in neuronal death. In light of this, several treatment modalities that modify components of proteostasis have shown promise in the management of neurological disorders. These include chemical chaperones to assist proper folding of proteins, inhibitors of overly active protein degradation, and enhancers of endogenous proteolytic pathways, such as the UPS. This review summarizes recent work on the pathomechanisms of abnormal protein folding and degradation in epilepsy, as well as treatment developments targeting this area.

Keywords: ER stress; chaperones; epilepsy; proteostasis; ubiquitin proteasome system.

Figure 1

Epilepsy is associated with changes in the ubiquitination and proteasomal degradation of proteins. Under normal physiological conditions, a ubiquitin-activating E1 enzyme hydrolyzes ATP to bind to ubiquitin (Ub), and then transfers the ubiquitin to a ubiquitin-conjugating E2 enzyme. The substrate-specific E3 ubiquitin ligase recognizes a protein and transfers the ubiquitin from the E2 enzyme to the substrate protein. A polyubiquitin chain can then be formed by adding to the initial ubiquitin. The 26S proteasome recognizes the ubiquitinated substrate and hydrolyzes it into small peptides. A deubiquitinase (DUB) removes the ubiquitin molecules before they can be degraded, so that they can be reused. However, in pathological states, such as those that occur in epilepsy, several steps of this process can be compromised, including downregulation or mutation of E3 ligases, impaired substrate recognition or ubiquitination, inappropriate DUB activity, and dysregulation of the proteasome itself. These steps are indicated by a red X.

Figure 2

Rescue of dysregulated proteostasis in epilepsy. (A) Under healthy conditions, there is appropriate expression and trafficking of proteins. Here, a membrane channel is shown as an example. (B) Insufficient protein degradation can occur in epilepsies, due to factors such as aggregation-prone mutants, decreased E3 ubiquitin ligase activity, or loss of deubiquitinase function. Potential rescue mechanisms include chaperones, to prevent aggregation of mutant proteins, and PROTACs, to enhance degradation of specific substrates. (C) Excessive protein degradation is also seen in epilepsies, when a mutant protein with only partial loss of function is not permitted to reach its final location, in order to exert a function. Chaperones may help the protein fold properly, allowing proper trafficking, as would inhibition of the select components involved in the degradation of that protein.