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.
Description
Keywords
Epilepsy, Wnt signaling, HBP1, Genetic Epilepsy, Epi4K, Epileptogensis, Astrocytes, Hippocampus, Pathological alterations in epilepsy