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.
Highlights
Proteins are crucial to nearly every function in a cell, including both the general functions found in nearly every cell, such as energy production and DNA replication, as well as neuron-specific processes, such as maintenance of the membrane potential and synaptic vesicle release
The function of the unfolded protein response (UPR) is to restore proteostasis, which can be aided by several mechanisms: boosting the folding capacity of the endoplasmic reticulum (ER) by enlarging the ER and upregulating chaperones; decreasing the number of proteins to fold via increased ER-to-Golgi trafficking and halted protein translation; and/or enhancing protein degradation [1,16,19]
Bingol and Shuman (2006) showed that, in cultured hippocampal neurons, acute NMDA receptor activation resulted in a greater number of proteasomes in dendritic spines, primarily due to a six-fold decrease in the rate at which proteasomes exited the spines, and aided by a subtler increase in the rate at which proteasomes were trafficked into the spines [32]
Summary
Proteins are crucial to nearly every function in a cell, including both the general functions found in nearly every cell, such as energy production and DNA replication, as well as neuron-specific processes, such as maintenance of the membrane potential and synaptic vesicle release. Up to one-third of newly synthesized proteins are degraded due to problems with synthesis or folding [1] This inefficiency can pose problems, as is the native protein function lost by the misfolding, toxic protein aggregates may form [1]. Neuronal function depends on a vast array of membrane proteins, such as voltage gated ion channels and neurotransmitter receptors and transporters, and membrane proteins in particular, are prone to rapid degradation, as their complex structure results in inefficient folding and assembly [2]. Protein degradation is a crucial function in cells, to properly balance protein synthesis and to eliminate misfolded or mutated proteins [9,10]. The UPS, which degrades the majority of intracellular proteins, primarily degrades individual proteins, as the target must be able to enter the narrow entrance of the proteasome [11,12] These two pathways are interconnected, as they rely on shared components, such as ubiquitin, and disruptions to one pathway can alter the other [9,11]. Dysfunction of the UPS is, associated with many diseases, ranging from cancer to neurological diseases, including epilepsy [9,12,14,15]
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