The Role of HBP1 and Wnt signaling in Genetic and Idiopathis Epilepsy

Abstract

Epilepsy is one of the most prevalent neurological diseases which results from abnormal neuronal firing, leading to the development of spontaneous recurrent seizures. Despite the development of multiple anti-epileptic medications in the last decade, about one third of the patients eventually develop resistant to anti-epileptic drugs. One of the most important reasons behind the drug resistance is the inability to identify a clear mechanistic pathway to be targeted for treatment. Existing pharmaceutical treatments function primarily to reduce hyper-excitability thus providing only symptomatic control. Identifying alternative mechanistic targets for anti-epileptic treatment to prevent the progression of chronic epilepsy has been the main research focus recently. The Yee lab has shown that the Wnt/β-catenin pathway is aberrantly activated in both acute and chronic epilepsy, driving a metabolic reprogramming of aerobic glycolysis (Warburg-like metabolism) resulting in elevated mTOR signaling. Key to these changes was phosphorylation-dependent inhibition of Pyruvate Dehydrogenase (PDH) by the Wnt target gene PDK4. One of the known inhibitors of Wnt signaling, HMG box protein 1 (HBP1), was shown to decline in the epileptogenic period, suggesting a mechanism for Wnt activation in epileptogenesis. As a test of this mechanism, HBP1 knockout mice had elevated Wnt signaling in the hippocampus and recapitulated the metabolic reprogramming to aerobic glycolysis (Warburg-like metabolism) and elevated mTOR signaling. In-depth analysis of gene and protein expression, bioinformatics and confocal microscopy suggested additional changes. Among these, we observed a reduction in multiple GABA receptors and increased glutamate receptor expression along with altered glutamate transport. These results were consistent with a remarkably altered susceptibility to seizure induction along with occasional spontaneous seizures in HBP1-/- mice. Accompanying the seizure phenotype we observed gliosis, which is consistent with seizure and the altered signaling and metabolic alterations. Collectively, these data provide evidence that HBP1 alterations/Wnt signaling may determine the threshold of acquired seizure susceptibility. Consistent with the mouse results, several genome-wide studies suggest a disruption of Wnt/β-catenin in epilepsy patients. Moreover, multiple case reports were published highlighting deletions within the genomic region of the HBP1 and its possible correlation with neurological diseases including autism, intellectual disability and epilepsy. Human genetic sequencing data were obtained from 1600 patients and family members in the Epi4K database yielded 8 HBP1 variants and a near-significant association with Lennox-Gastault epilepsy tied to a specific variant (R375P). Mutagenesis experiments to evaluate the functional impact of these variants on HBP1 protein function demonstrated that R375P was disruptive, resulting in HBP1R375P failing to repress Wnt activity. These data suggest that loss of HBP1 function through deletion or mutation results in susceptibility to epilepsy.