Trim-mediated ubiquitin signaling in epilepsy: From synaptic dysregulation to neuroinflammatory network remodeling

Epilepsy is a chronic neurological disorder characterized by a persistent predisposition to spontaneous, recurrent seizures arising from aberrant, hypersynchronous neuronal activity. Over 50 million people in the world have epilepsy, which remains one of the leading causes of neurological morbidity. Complex disturbances in neuronal homeostasis, most notably an imbalance of excitatory glutamatergic and inhibitory GABAergic neurotransmission, together with synaptic remodeling, neuroinflammation, oxidative stress, and impaired protein quality control, are the molecular causes of epileptogenesis. According to new research, dysregulation of the ubiquitin-proteasome system (UPS), which influences the turnover of ion channels, neurotransmitter receptors, and signaling proteins that regulate neuronal excitability, is an essential factor in seizure susceptibility. In this context, the large family of RING-type E3 ubiquitin ligases called tripartite motif (TRIM) proteins has attracted interest as essential regulators for immunological signaling, redox homeostasis, synaptic stability, and neuronal stress responses. Several TRIM members are enriched in the central nervous system and affect interneuron development, glutamate receptor trafficking, gamma-aminobutyric acid (GABAergic) inhibitory tone, and seizure-induced neuroinflammatory cascades. This brings them to the intersection of excitatory-inhibitory imbalance and epileptic network remodeling. This review integrates mechanistic insights into the link between TRIM-mediated ubiquitination and epileptogenesis with current knowledge of TRIM protein structure and function. In addition, it identifies current barriers, knowledge gaps, and potential future directions for TRIM-based interventions in epilepsy, the tripartite motif (TRIM) proteins, has attracted attention as important regulators of as well as new preclinical and translational evidence supporting TRIM proteins as potential therapeutic targets.