Biology subjects

Hedrich, U. B. S.

Publications and source records attributed to Hedrich, U. B. S..

8 recordsLinked to original sources

bioRxiv2026

Scorpion toxin peptide BMK86-P1 achieves mutation-reversible inhibition of KCNA2 at the cost of reduced efficacy in heteromers and murine neurons

The discovery of distinctive function-phenotype relationships in monogenetic channelopathies has turned out to be critical for the development of precision medicine approaches. However, the best prediction of clinical phenotypes depends on neuronal function, where existing models lack tools to isolate currents of individual voltage-gated potassium channel subunits and differentiate variant effects in complex systems. Ideally, one should be able to overexpress subunit variants with an additional mutation that confers resistance against the tool to isolate the variant effect. Therefore, we solid-phase synthesized the KV1.2 specific scorpion toxin peptide BMK86-P1 and oxidized it with modest efficacy. In mammalian cells this BMK86-P1 selectively inhibited KV1.2 homomers, but not heteromers with KV1.1. Critically, the KCNA2 p.Val381Tyr mutation, which reverses BMK86-P1's selective inhibition of KV1.2, also altered the activation of KV1.2 homomers to resemble those of KV1.1. In addition, BMK86-P1 in murine neurons did not alter passive membrane properties, single action potential properties, or action potential firing. Surprisingly, it induced only minimal changes in spontaneous excitatory postsynaptic currents. In summary, this KV1.2 subunit selective toxin peptide asserts its effects primarily on homomeric channels, while only weakly inhibiting KV1.2-heteromeric channels and consequently preventing any meaningful impact on neuronal function. This highlights the limits of peptide synthesis together with the need for testing specific compounds on complex systems.

neuroscience↗

bioRxiv2025

Oligodendrocyte precursor cells establish regulatory contacts with the soma of active neurons

Oligodendrocyte precursor cells (OPCs) generate myelinating oligodendrocytes and interact with synapses to regulate neuronal networks. Neuronal activity induces proliferation or differentiation of OPCs, but it is unknown whether OPCs in turn affect neuronal activity. Here, we show that OPCs establish close contacts with the somata of active neurons. We found that neurons contacted by OPCs and their processes display reduced calcium signals, indicating that they regulate their activity.

neuroscience↗

bioRxiv2023

Axonopathy and altered synaptic development in early hippocampal epileptogenesis of Dravet syndrome

Dravet syndrome caused by SCN1A variants is a severe developmental epileptic encephalopathy (DEE) characterized by pharmaco-resistant epileptic seizures and progressive neurodevelopmental decline with cognitive impairment and autism-spectrum-traits. Numerous preceding studies indicate that the initial pathophysiology due to impaired NaV1.1 function mainly derives from reduced interneuron firing leading to a network hyperexcitability (Bender et al. 2012). However, little is known how epileptogenesis and generally disease pathogenesis progress from the inborn molecular defect to infantile seizure onset. We address this question in a Dravet mouse model by comprehensive single-cell RNA sequencing and selected downstream analysis via single-cell electrophysiology, histology, live cell imaging and electron microscopy. Our data reveal a continuum of early primary (preseizure) and secondary (post-seizure onset) transcriptomic changes in various cell populations in the hippocampus. Focusing on cornu ammonis, we find a number of transcriptional pathways that are dysregulated including synaptic transmembrane adhesion molecules of the neurexin superfamily and voltage-gated ion channels. Further investigations support an ultrastructural and functional axonopathy and synaptopathy of parvalbumin interneurons. These processes precede somatic firing impairment and seizures suggesting they underlie fundamental early-phase disease mechanisms. Taken together we provide a cellularly resolved transcriptomic resource of early disease phases of Dravet syndrome and demonstrate epileptogenesis beyond NaV1.1 loss-of-function during an early developmental time window of CNS maturation. Altogether these data establish proof-of principle that the concept of epileptogenesis, originally devised for acquired forms of epilepsy, similarly applies to genetic epilepsies and DEEs.

neuroscience↗

bioRxiv2023

Loss or Gain of Function? Neuronal Firing Effects of Ion Channel Mutations Depend on Cell Type

Clinically relevant mutations to voltage-gated ion channels, called channelopathies, alter ion channel function, properties of ionic current and neuronal firing. The effects of ion channel mutations are routinely assessed and characterized as loss of function (LOF) or gain of function (GOF) at the level of ionic currents. Emerging personalized medicine approaches based on LOF/GOF characterization have limited therapeutic success. Potential reasons are that the translation from this binary characterization to neuronal firing especially when considering different neuronal cell types is currently not well understood. Here we investigate the impact of neuronal cell type on the firing outcome of ion channel mutations with simulations of a diverse collection of neuron models. We systematically analyzed the effects of changes in ion current properties on firing in different neuronal types. Additionally, we simulated the effects of mutations in the KCNA1 gene encoding the KV1.1 potassium channel subtype associated with episodic ataxia type 1 (EA1). These simulations revealed that the outcome of a given change in ion channel properties on neuronal excitability is cell-type dependent. As a result, cell-type specific effects are vital to a full understanding of the effects of channelopathies on neuronal excitability and present an opportunity to further the efficacy and precision of personalized medicine approaches. Significance StatementAlthough the genetic nature of ion channel mutations as well as their effects on the biophysical properties of an ion channel are routinely assessed experimentally, determination of their role in altering neuronal firing is more difficult. In particular, cell-type dependency of ion channel mutations on firing has been observed experimentally, and should be accounted for. In this context, computational modelling bridges this gap and demonstrates that the cell type in which a mutation occurs is an important determinant in the effects of neuronal firing. As a result, classification of ion channel mutations as loss or gain of function is useful to describe the ionic current but should not be blindly extend to classification at the level of neuronal firing.

neuroscience↗

bioRxiv2022

Learning with phenotypic similarity improves the prediction of functional effects of missense variants in voltage-gated sodium channels

BackgroundMissense variants in genes encoding voltage-gated sodium channels are associated with a spectrum of severe diseases affecting neuronal and muscle cells, the so-called sodium channelopathies. Variant effects on the biophysical function of the channel correlate with clinical features and can in most cases be categorized as an overall gain- or loss-of-function. This information enables a timely diagnosis, facilitates precision therapy, and guides prognosis. Machine learning models may be able to rapidly generate supporting evidence by predicting variant functional effects. MethodsHere, we describe a novel multi-task multi-kernel learning framework capable of harmonizing functional results and structural information with clinical phenotypes. We included 62 sequence- and structure-based features such as amino acid physiochemical properties, substitution radicality, conservation, protein-protein interaction sites, expert annotation, and others. We harmonized phenotypes as human phenotype ontology (HPO) terms, and compared different measures of phenotypic similarity under simulated sparsity or noise. The final model was trained on whole-cell patch-clamp recordings of 375 unique non-synonymous missense variants each expressed in mammalian cells. ResultsOur gain- or loss-of-function classifier outperformed both conventional baseline and state-of-the-art methods on internal validation (mean accuracy 0.837 {+/-} 0.035, mean AU-ROC 0.890 {+/-} 0.023) and on an independent set of recently described variants (n = 30, accuracy 0.967, AU-ROC 1.000). Model performance was robust across different phenotypic similarity measures and largely insensitive to phenotypic noise or sparsity. Localized multi-kernel learning offered biological insight and interpretability by highlighting channels with implicit genotype-phenotype correlations or latent task similarity for downstream analysis. ConclusionsLearning with phenotypic similarity makes efficient use of clinical information to enable accurate and robust prediction of variant functional effects. Our framework extends the use of human phenotype ontology terms towards kernel-based methods in machine learning. Training data, pre-trained models, and a web-based graphical user interface for the model are publicly available.

bioinformatics↗

bioRxiv2021

Modulating effects of FGF12 variants on NaV1.2 and NaV1.6 associated with Developmental and Epileptic Encephalopathy and Autism Spectrum Disorder

ObjectiveFibroblast growth factor 12 (FGF12) may represent an important modulator of neuronal network activity and has been associated with developmental and epileptic encephalopathy (DEE). We sought to identify the underlying pathomechanism of FGF12-related disorders. MethodsPatients with pathogenic variants in FGF12 were identified through published case reports, GeneMatcher and whole exome sequencing of own case collections. The functional consequences of two missense variants and two copy number variants (CNVs) were studied by co-expression of wild-type and mutant FGF12 in neuronal-like cells (ND7/23) with the sodium channels NaV1.2 or NaV1.6, including their functional active beta-1 and beta-2 sodium channel subunits (SCN1B and SCN2B). ResultsFour variants in FGF12 were identified for functional analysis: one novel FGF12 variant in a patient with autism spectrum disorder and three variants from previously published patients affected by developmental and epileptic encephalopathy (DEE). We demonstrate the differential regulating effects of wildtype and mutant FGF12 on NaV1.2 and NaV1.6 channels. Here, FGF12 variants lead to a complex kinetic influence on Nav1.2 and Nav 1.6, including loss- as well as gain-of function changes in fast inactivation as well as loss-of function changes in slow inactivation. InterpretationFor the first time, we could demonstrate the detailed regulating effect of FGF12 on NaV1.2 and NaV1.6 and confirmed the complex effect of FGF12 on neuronal network activity. Our findings expand the phenotypic spectrum related to FGF12 variants and elucidate the underlying pathomechanism. Specific variants in FGF12-associated disorders may be amenable to precision treatment with sodium channel blockers.

neuroscience↗

bioRxiv2021

Predicting the functional effects of voltage-gated potassium channel missense variants with multi-task learning

PurposeVariants in genes encoding voltage-gated potassium channels are associated with a broad spectrum of neurological diseases including epilepsy, ataxia, and intellectual disability. Knowledge of the resulting functional changes, characterized as overall ion channel gain- or loss-of-function, is essential to guide clinical management including precision medicine therapies. However, for an increasing number of variants, little to no experimental data is available. New tools are needed to evaluate variant functional effects. MethodsWe catalogued a comprehensive dataset of 959 functional experiments across 19 voltage-gated potassium channels, leveraging data from 782 unique disease-associated and synthetic variants. We used these data to train a taxonomy-based multi-task learning support vector machine (MTL-SVM), and compared performance to a baseline of standard SVMs. ResultsMTL-SVM maintains channel family structure during model training, improving overall predictive performance (mean balanced accuracy 0.729 {+/-} 0.029, AU-ROC 0.757 {+/-} 0.039) over baseline (mean balanced accuracy 0.645 {+/-} 0.041, AU-ROC 0.710 {+/-} 0.074). We can obtain meaningful predictions even for channels with few known variants (KCNC1, KCNQ5). ConclusionOur model enables functional variant prediction for voltage-gated potassium channels. It may assist in tailoring current and future precision therapies for the increasing number of patients with ion channel disorders.

bioinformatics↗

bioRxiv2021

In vitro effects of S-Licarbazepine as a potential precision therapy on SCN8A variants causing neuropsychiatric disorders

Background and PurposeAmong genetic epilepsies, variants in sodium channel coding genes constitute a major subgroup. Variants in SCN8A, the coding gene for NaV1.6 channels, are characterized by a variety of symptoms including intractable epileptic seizures, psychomotor delay, progressive cognitive decline, and others such as autistic features, ataxia or dystonia. Standard anticonvulsant treatment has only limited impact on the course of disease. Experimental ApproachPersonalized therapeutic regimens tailored to disease-causing pathophysiological mechanisms may offer the specificity required to overcome intractability. Toward this aim, we investigated in vitro in neuroblastoma cells the effects of S-Licarbazepine, a third-generation dibenzazepine and enhancer of slow inactivation of voltage gated sodium channels, on three gain-of-function NaV1.6 variants linked to representative phenotypes of mild epilepsy (G1475R), developmental and epileptic encephalopathy (M1760I) and intellectual disability without epilepsy (A1622D). Key ResultsS-Licarbazepine strongly enhances the slow and - less pronounced - the fast inactivation of NaV1.6 wildtype channels. It acts similarly on all tested variants and irrespective of their particular biophysical dysfunction mechanism. Beyond that S-Licarbazepine has variant-specific effects including a partial reversal of pathologically slowed fast inactivation dynamics (A1622D, M1760I) and a trend to reduce the enhanced persistent Na+ current by A1622D variant channels. Conclusion and ImplicationsThese data bring out that S-Licarbazepine not only owns substance-specific effects, but also holds variant-specific effects, which can variably contribute to functional compensation of distinct channel-specific biophysical properties and thereby highlighting the role of personalized approaches, which likely will be key to improved and successful treatment not only of SCN8A-related disease. Bullet pointsO_LIWhat is already known? S-Lic strongly modulates slow and - to a less extend - fast inactivation of wild-type NaV1.6 channels. C_LIO_LIWhat this study adds? Differential modulatory effects of S-Lic extend to NaV1.6 A1622D, M1760I and G1475R variant channels irrespective of their leading biophysical mode of gain-of-function and variably contribute to variant-specific functional compensation of their altered biophysical properties. C_LIO_LIClinical significance: These data suggest therapeutic potential of S-Lic for SCN8A neuropsychiatric disorders and highlight the role of personalized approaches aimed at increasingly precise correction of underlying pathophysiological mechanisms. C_LI

pharmacology and toxicology↗