Ubiquitin Proteasome System BTB-Adaptor Protein Insomniac Modifies Seizure Severity and Response to the Ketogenic Diet in a Drosophila Model of Mitochondrial Encephalomyopathy.
- 1Department of Pharmacology & Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA.
- 2Pittsburgh Institute for Neurodegenerative Diseases, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA.
Abstract
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. Methods: We utilized a genetic approach to interrogate neurobehavioral dysfunction in mitochondrial encephalomyopathy (ME) and the ability of dietary therapy to modulate this dysfunction. Results: Here, we report that genetic interference with insomniac modifies seizure-like behavior in a neuronal-subtype-specific manner in the ATP6¹ model of ME, ameliorating seizure severity when knocked down in GABAergic or dopaminergic neurons. Furthermore, while ATP6¹ typically responds to ketogenic dietary therapy with a robust reduction in seizure phenotype, we report that knockdown of insomniac or its binding partner Cullin RING Ligase 3 (Cul3) in neurons ablates this effect entirely, a previously unreported role for the UPS in downstream neurophysiological effects of the KD. Conclusions: These results implicate UPS BTB adaptor proteins as therapeutic targets in seizure pathology and identify them as a novel contributor to the ketogenic suppression of neuronal hyperexcitability. These two neurological roles are likely to be proceeding via cellular and molecularly distinct pathways, including a non-CRL3-based mechanism of seizure modulation.
Related
- The Proliferation–Invasion Dichotomy: Transcriptomic Signatures of lncRNA and Ubiquitin–Proteasome Networks in Hypermutated Endometrial Cancer
- Targeting ubiquitin-dependent mitochondrial autophagy and apoptosis in sarcopenia: the therapeutic potential of phytochemicals.
- Co-administration of simvastatin mitigates clozapine-induced lifespan extension and mitochondrial functional recovery in Drosophila melanogaster.
- Integrated bioinformatic analysis identifies distinct neddylation-associated proteasome genes and immune-related features in laryngeal squamous cell carcinoma
- Targeting proteasome composition reprograms tumor-intrinsic inflammation through selective degradation of STAT1
BibTeX
@article{fogle2026ubiquitin,
title = {{Ubiquitin Proteasome System BTB-Adaptor Protein Insomniac Modifies Seizure Severity and Response to the Ketogenic Diet in a Drosophila Model of Mitochondrial Encephalomyopathy.}},
author = {Keri J Fogle and Brynn Urban and Dana M Mumford and Michael J Palladino},
journal = {Genes},
year = {2026},
month = sep,
doi = {10.3390/genes17101185},
url = {https://europepmc.org/article/MED/42938300},
note = {CC BY},
}
RIS
TY - JOUR
TI - Ubiquitin Proteasome System BTB-Adaptor Protein Insomniac Modifies Seizure Severity and Response to the Ketogenic Diet in a Drosophila Model of Mitochondrial Encephalomyopathy.
AU - Keri J Fogle
AU - Brynn Urban
AU - Dana M Mumford
AU - Michael J Palladino
PY - 2026
DA - 2026/09/24
JO - Genes
DO - 10.3390/genes17101185
UR - https://europepmc.org/article/MED/42938300
AB - 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. Methods: We utilized a genetic approach to interrogate neurobehavioral dysfunction in mitochondrial encephalomyopathy (ME) and the ability of dietary therapy to modulate this dysfunction. Results: Here, we report that genetic interference with insomniac modifies seizure-like behavior in a neuronal-subtype-specific manner in the ATP6¹ model of ME, ameliorating seizure severity when knocked down in GABAergic or dopaminergic neurons. Furthermore, while ATP6¹ typically responds to ketogenic dietary therapy with a robust reduction in seizure phenotype, we report that knockdown of insomniac or its binding partner Cullin RING Ligase 3 (Cul3) in neurons ablates this effect entirely, a previously unreported role for the UPS in downstream neurophysiological effects of the KD. Conclusions: These results implicate UPS BTB adaptor proteins as therapeutic targets in seizure pathology and identify them as a novel contributor to the ketogenic suppression of neuronal hyperexcitability. These two neurological roles are likely to be proceeding via cellular and molecularly distinct pathways, including a non-CRL3-based mechanism of seizure modulation.
SN - 2073-4425
ER -