Ubiquitin Proteasome System BTB-Adaptor Protein Insomniac Modifies Seizure Severity and Response to the Ketogenic Diet in a Drosophila Model of Mitochondrial Encephalomyopathy

Background/Objectives: The ubiquitin proteasome system (UPS) serves critical cellular homeostatic functions that contribute to neurological health, including neuronal metabolism, synaptic plasticity, and the molecular circadian clock. The UPS is tightly regulated to ensure the correct balance of healthy proteins and those targeted for degradation and recycling; malfunction in this quality control process can contribute to disease states such as neurodegeneration and cancer. Target specificity in this system is due in part to ubiquitin ligase adaptor proteins, such as those of the BTB superfamily of proteins, which connect substrates to the larger proteasomal complex. In Drosophila, the BTB family member insomniac (human orthologs KTCD2, 5, and 17) has been shown to regulate sleep, arousal, and synaptic plasticity, but has not been examined for a role in neuronal excitability disease phenotypes.