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.

The “Cerebrospinal Fluid Sink Therapeutic Strategy” in Alzheimer’s Disease—From Theory to Design of Applied Systems

“…Protein degradation can occur at both the intra- and extracellular levels via different mechanisms. Other recent works have already reviewed the role of intracellular systems including the ubiquitin−proteasome [ 46 ], autophagy−lysosome [ 47 ], and endosome–lysosome pathways [ 48 ] in physiological conditions and in neurological disorders, when they are altered. Similarly, extracellular degradation occurs via protease action and microglia or astrocyte phagocytosis, being significantly reduced in pathological conditions such as AD [ 49 ].…”

Pharmacological chaperones restore proteostasis of epilepsy-associated GABAAreceptor variants

“…One major disease-causing mechanism for the loss of function of GABA A receptors is that pathogenic variants lead to receptor trafficking deficiencies due to defective protein conformations 6,19 . Such epilepsy-associated GABA A receptor subunit variants cause protein misfolding and/or disrupt the subunit-subunit assembly process in the ER, resulting in a decrease in the surface expression of the pentameric receptors.…”

Pathogenicity Prediction of GABAAReceptor Missense Variants

“…However, the clinical significance of these variants is not adequately addressed since most of them lack functional characterization and many of them are classified as uncertain or conflicting interpretations. For the limited number of characterized GABA A receptor variants, accumulating evidence indicated that proteostasis deficiency that resulted from misfolding and excessive degradation of the variants is a major disease-causing mechanism [13] . Adapting the ER proteostasis network pharmacologically corrected the misfolding and restored the surface trafficking and thus ion channel function for a variety of pathogenic GABA A receptor variants [14] .…”