LAUSR

Commentary Tightly regulated protein homeostasis is essential for neuronal function. In response to external stimuli, proteins are constantly added to and removed from synapses. The dynamic regulation of synaptic and neuronal protein content is achieved by protein synthesis, trafficking, and degradation. Defects in these processes have been associated with numerous brain disorders, including epilepsy. For many years, the major attention in epilepsy research has been on mechanisms that regulate the synthesis of proteins, such as mRNA transcription and translation. More recently, mechanisms that regulate the targeted removal of proteins—for example, through the ubiquitin proteasome system (UPS)—have become a focus of interest. Increased seizure susceptibility has been linked to gene mutations or aberrant expression of enzymes mediating protein ubiquitination (1–4), which tags proteins for their degradation by the proteasome (5). However, little is known about the specific proteins and mechanisms that are affected by a dysfunctional UPS in epilepsy. The study by Zhu, Tsai, and colleagues is noteworthy because it is one of the first to shed light on the molecular mechanisms leading to heightened seizure susceptibility when a component of the UPS, the epilepsy-associated neural precursor cell expressed, developmentally down-regulated 4 (Nedd4-2), is impaired. Nedd4-2 belongs to the large family of E3 ubiquitin ligases that are essential for ubiquitination. They covalently and target-specifically attach a 76-amino acid polypeptide called “ubiquitin” to certain lysines in proteins, providing a high degree of substrate diversity and specificity. Ubiquitin itself can be ubiquitinated, often giving rise to branched polyubiquitin chains. This polyubiquitination marks proteins for degradation by the proteasome, a multi-subunit complex that functions as the cell’s internal disposal system for proteins. To complicate matters, ubiquitination is reversible through deubiquitinating enzymes, and not every polyubiquitinated protein will be degraded. Instead, ubiquitination can also label a protein for membrane internalization or target it to certain organelles (5). Nedd4-2 has been discovered as an epilepsy susceptibility gene a few years ago, including photosensitive epilepsy and epileptic encephalopathies (3, 4), but the underlying mechanisms have been obscure. The study by Zhu et al. is an important advance because it is the first report of a protein substrate of Nedd4-2 that may contribute to the epilepsy phenotype when Nedd4-2 is mutated. Using pharmacologic and genetic tools, the authors provided several lines of evidence that the GluA1 subunit of the AMPA receptor, a known target of Nedd4Epilepsy-Associated Gene Nedd4-2 Mediates Neuronal Activity and Seizure Susceptibility Through AMPA Receptors.