Biology subjects

Morton, C.

Publications and source records attributed to Morton, C..

10 recordsLinked to original sources

bioRxiv2025

Exaggerated NMDA Receptor-Primed Metaplasticity via SK Channel Dysregulation in Fmr1 Knockout Mice

Fragile X syndrome (FXS), the most common monogenic neurodevelopmental disorder associated with autism and intellectual disability, results from the loss of expression of the FMR1 gene. Synaptic and circuit-level abnormalities are well documented in FXS and extensively studied in the Fmr1 KO mouse model. In CA1 hippocampal neurons functional, molecular and structural synaptic changes have been described yet the canonical form of Hebbian CA1 long term potentiation (LTP) remains intact in Fmr1 KO mice. Here we examined whether state-dependent synaptic plasticity in CA1, in which prior "priming" activity modulates subsequent synaptic plasticity, was affected in Fmr1 KO mice. We found that NMDA receptor activation prior to LTP induction produced metaplastic inhibition of LTP, which was exaggerated in Fmr1 KO mice. This effect was mediated by the activity of small conductance calcium-activated potassium (SK) channels which was enhanced after NMDA priming, and dampened dendritic excitability. Blocking SK channels during NMDA-primed LTP induction eliminated the abnormal metaplasticity in Fmr1 KO slices, implicating altered SK activity in the exaggerated LTP inhibition in Fmr1 KO mice. These finding reveal a disrupted coupling between NMDA receptors and SK channels in Fmr1 KO mice, which alters the impact of priming on LTP expression in the CA1. Altered metaplasticity may represent a neural correlate of impaired adaptive hippocampal learning in Fmr1 KO mice. Significance StatementWhile conventional synaptic plasticity (LTP and LTD) has been extensively examined in Fmr1 KO mice, evidence about the integrity of metaplasticity in these mice has been limited. This study provides a characterization of alterations in NMDA receptor mediated metaplasticity in the hippocampus in Fmr1 KO mice. The question of whether hippocampal LTP is altered in these mice remains unresolved, and changes in metaplasticity may partly explain the discrepancies across studies. Our findings not only identify novel synaptic phenotypes and their underlying mechanisms in the FXS mouse model, but also highlight potential therapeutic targets for FXS.

neuroscience↗

bioRxiv2025

Natural product-mediated reaction hijacking mechanism validates Plasmodium aspartyl-tRNA synthetase as an antimalarial drug target

Malaria poses an enormous threat to human health. With ever-increasing resistance to currently deployed antimalarials, new targets and starting point compounds with novel mechanisms of action need to be identified. Here, we explore the antimalarial activity of the Streptomyces sp natural product, 5'-O-sulfamoyl-2-chloroadenosine (dealanylascamycin, DACM) and compare it with the synthetic adenosine monophosphate (AMP) mimic, 5-O-sulfamoyladenosine (AMS). These nucleoside sulfamates exhibit potent inhibition of P. falciparum growth with an efficacy comparable to that of the current front-line antimalarial dihydroartemisinin. Exposure of P. falciparum to DACM leads to inhibition of protein translation, driven by eIF2 phosphorylation. We show that DACM targets multiple amino acyl tRNA synthetase (aaRS) targets, including the cytoplasmic aspartyl tRNA synthetase (AspRS). The mechanism involves hijacking of the reaction product, leading to the formation of a tightly bound inhibitory amino acid-sulfamate conjugate. We show that recombinant P. falciparum and P. vivax AspRS are susceptible to hijacking by DACM and AMS, generating Asp-DACM and Asp-AMS adducts that stabilize these proteins. By contrast, human AspRS appears less susceptible to hijacking. X-ray crystallography reveals that apo P. vivax AspRS exhibits a stabilized flipping loop over the active site that is poised to bind substrates. By contrast, human AspRS exhibits disorder in an extended region around the flexible flipping loop as well as in a loop in motif II. These structural differences may underpin the decreased susceptibility of human AspRS to reaction-hijacking by DACM and AMS. Our work reveals Plasmodium AspRS as a promising antimalarial target and highlights structural features that underpin differences in the susceptibility of aaRSs to reaction hijacking inhibition.

biochemistry↗

bioRxiv2025

Near-atomic structure of the PorKN rings, disulfide bonded to PorG and bound to Attachment Complexes, provide mechanistic insights into the type IX secretion system

The Type IX Secretion System exports proteins across the outer membrane (OM) of bacteria in the Bacteroidota phylum, however, the mechanistic details remain unknown. Here, we present a [~]3.5[A] cryo-EM structure of the periplasmic rings comprising 32-33 subunits each of PorK and PorN. Additionally, we show the presence of a critical disulfide bond between PorK and the PorG OM protein that is essential for protein secretion and demonstrate that the Attachment Complexes bind to and are localized above the PorKN rings. Overall, each ring resembles a cogwheel with PorN forming cog-like projections on the periplasmic side and the flat surface of PorK orienting towards the OM. Given these results, we propose that the PorLM motor drives the rotation of the PorKN cogwheel together with PorG and associated Attachment Complexes, potentially providing the energy to complete protein secretion and the coordinated cell surface attachment of the secreted cargo.

microbiology↗

bioRxiv2025

A vector-based strategy for olfactory navigation in Drosophila

Odors serve as essential cues for navigation. Although tracking an odor plume has been modeled as a reflexive process, it remains unclear whether animals can use memories of their past odor encounters to infer the spatial structure of their chemical environment or their location within it. Here we developed a virtual-reality olfactory paradigm that allows head-fixed Drosophila to navigate structured chemical landscapes, offering insight into how memory mechanisms shape their navigational strategies. We found that flies track an appetitive odor corridor by following its boundary, alternating between rapid counterturns to exit the plume and directed returns to its edge. Using a combination of behavioral modeling, functional calcium imaging, and neural perturbations, we demonstrate that this edge-tracking strategy relies on vector-based computations within the Drosophila central complex in which flies store and dynamically update memories of the direction to return them to the plumes boundary. Consistent with this, we find that FC2 neurons within the fan-shaped body, which encode a flys navigational goal, signal the direction back to the odor boundary when flies are outside the plume. Together, our studies suggest that flies leverage the plumes boundary as a dynamic landmark to guide their navigation, analogous to the memory-based strategies other insects use for long-distance migration or homing to their nests. Plume tracking thus uses components of a conserved navigational toolkit, enabling flies to use memory mechanisms to navigate through a complex shifting chemical landscape.

neuroscience↗

bioRxiv2024

Real-time prediction of drug-induced proarrhythmic risk with sex-specific cardiac emulators

In silico trials for drug safety assessment require a large number of high-fidelity 3D cardiac electrophysiological simulations to predict drug-induced QT interval prolongation, making the process computationally expensive and time-consuming. These simulations, while necessary to accurately model the complex physiological conditions of the human heart, are often cost-prohibitive when scaled to large populations or diverse conditions. To overcome this challenge, we develop sex-specific emulators for the real-time prediction of QT interval prolongation, with separate models for each sex. Building an extensive dataset from 900 simulations allows us to show the superior sensitivity of 3D models over 0D single-cell models in detecting abnormal electrical propagation in response to drug effects as the risk level increases. The resulting emulators trained on this dataset showed high accuracy level, with an average relative error of 4% compared to simulation results. This enables global sensitivity analysis and the replication of in silico cardiac safety clinical trials with accuracy comparable to that of simulations when validated against in vivo data. With our emulators, we carry out in silico clinical trials in seconds on a standard laptop, drastically reducing computational time compared to traditional high-performance computing methods. This efficiency enables the rapid testing of drugs across multiple concentration ranges without additional computational cost. This approach directly addresses several key challenges faced by the biopharmaceutical industry: optimizing trial designs, accounting for variability in biological assays, and enabling rapid, cost-effective drug safety evaluations. By integrating these emulators into the drug development process, we can enhance the reliability of preclinical assessments, streamline regulatory submissions, and advance the practical application of digital twins in biomedicine. This work represents a significant step toward more efficient and personalized drug development, ultimately benefiting patient safety and accelerating the path to market.

pharmacology and toxicology↗

bioRxiv2024

RBM39 degrader invigorates natural killer cells to eradicate neuroblastoma despite cancer cell plasticity

The cellular plasticity of neuroblastoma is defined by a mixture of two major cell states, adrenergic (ADRN) and mesenchymal (MES), which may contribute to therapy resistance. However, how neuroblastoma cells switch cellular states during therapy remains largely unknown and how to eradicate neuroblastoma regardless of their cell states is a clinical challenge. To better understand the lineage switch of neuroblastoma in chemoresistance, we comprehensively defined the transcriptomic and epigenetic map of ADRN and MES types of neuroblastomas using human and murine models treated with indisulam, a selective RBM39 degrader. We showed that cancer cells not only undergo a bidirectional switch between ADRN and MES states, but also acquire additional cellular states, reminiscent of the developmental pliancy of neural crest cells. The lineage alterations are coupled with epigenetic reprogramming and dependency switch of lineage-specific transcription factors, epigenetic modifiers and targetable kinases. Through targeting RNA splicing, indisulam induces an inflammatory tumor microenvironment and enhances anticancer activity of natural killer cells. The combination of indisulam with anti-GD2 immunotherapy results in a durable, complete response in high-risk transgenic neuroblastoma models, providing an innovative, rational therapeutic approach to eradicate tumor cells regardless of their potential to switch cell states.

cancer biology↗

bioRxiv2023

Nuclear receptor signaling via NHR-49/MDT-15 regulates stress resilience and proteostasis in response to reproductive and metabolic cues

The ability to sense and respond to proteotoxic insults declines with age, leaving cells vulnerable to chronic and acute stressors. Reproductive cues modulate this decline in cellular proteostasis to influence organismal stress resilience in C. elegans. We previously uncovered a pathway that links the integrity of developing embryos to somatic health in reproductive adults. Here, we show that the nuclear receptor NHR-49, a functional homolog of mammalian peroxisome proliferator-activated receptor alpha (PPAR), regulates stress resilience and proteostasis downstream of embryo integrity and other pathways that influence lipid homeostasis, and upstream of HSF-1. Disruption of the vitelline layer of the embryo envelope, which activates a proteostasis-enhancing inter-tissue pathway in somatic tissues, also triggers changes in lipid catabolism gene expression that are accompanied by an increase in fat stores. NHR-49 together with its co-activator MDT-15 contributes to this remodeling of lipid metabolism and is also important for the elevated stress resilience mediated by inhibition of the embryonic vitelline layer as well as by other pathways known to change lipid homeostasis, including reduced insulin-like signaling and fasting. Further, we show that increased NHR-49 activity is sufficient to suppress polyglutamine aggregation and improve stress resilience in an HSF-1-dependent manner. Together, our results establish NHR-49 as a key regulator that links lipid homeostasis and cellular resilience to proteotoxic stress.

genetics↗

bioRxiv2021

Single-molecule analysis of the entire perfringolysin O poreformation pathway

The cholesterol-dependent cytolysin perfringolysin O (PFO) is secreted by Clostridium perfringens as a bacterial virulence factor able to form giant ring-shaped pores that perforate and ultimately lyse mammalian cell membranes. To resolve the kinetics of all steps in the assembly pathway, we have used single-molecule fluorescence imaging to follow the dynamics of PFO on dye-loaded liposomes that lead to opening of a pore and release of the encapsulated dye. Formation of a long-lived membrane-bound PFO dimer nucleates the growth of an irreversible oligomer. The growing oligomer can insert into the membrane and open a pore at stoichiometries ranging from tetramers to full rings ([~]35-mers), whereby the rate of insertion increases linearly with the number of subunits. Oligomers that insert before the ring is complete continue to grow by monomer addition post insertion. Overall, our observations suggest that PFO membrane insertion is kinetically controlled.

biophysics↗

bioRxiv2021

Focused Ultrasound Modulation of Hepatic Neural Plexus Restores Glucose Homeostasis in Diabetes

While peripheral glucose sensors are known to relay signals of substrate availability to integrative nuclei in the brain, the importance of these pathways in maintaining energy homeostasis and their contribution to disease remain unknown. Herein, we demonstrate that selective activation of the hepatoportal neural plexus via transient peripheral focused ultrasound (pFUS) induces glucose homeostasis in models of well-established insulin resistant diabetes. pFUS modulates sensory projections to the hindbrain and alters hypothalamic concentrations of neurotransmitters that regulate metabolism, resulting in potentiation of hypothalamic insulin signaling, leptin-independent inhibition of the orexigenic neuropeptide Y system, and therapeutic alteration in autonomic output to peripheral effector organs. Multiomic profiling confirms pFUS-induced modifications of key metabolic functions in liver, pancreas, muscle, adipose, kidney, and intestines. Activation of the hepatic nutrient sensing pathway not only restores nervous system coordination of peripheral metabolism in three different species but does so across these organ systems; several of which are current targets of antidiabetic drug classes. These results demonstrate the potential of hepatic pFUS as a novel/non-pharmacologic therapeutic modality to restore glucose homeostasis in metabolic diseases, including type II diabetes. One Sentence SummaryWe utilize a non-invasive ultrasound technique to activate a liver-brain sensory pathway and demonstrate its potential to induce durable normalization of glucose homeostasis in models of well-established insulin resistant diabetes.

biophysics↗

bioRxiv2019

Genomic landscape of 261 childhood cancer patient-derived xenograft models

Accelerating cures for children with cancer remains an immediate challenge due to extensive oncogenic heterogeneity between and within histologies, distinct molecular mechanisms evolving between diagnosis and relapsed disease, and limited therapeutic options. To systematically prioritize and rationally test novel agents in preclinical murine models, researchers within the Pediatric Preclinical Testing Consortium are continuously developing patient-derived xenografts (PDXs) from high-risk childhood cancers, many refractory to current standard-of-care treatments. Here, we genomically characterize 261 PDX models from 29 unique pediatric cancer malignancies and demonstrate faithful recapitulation of histologies, subtypes, and refine our understanding of relapsed disease. Expression and mutational signatures are used to classify tumors for TP53 and NF1 inactivation, as well as impaired DNA repair. We anticipate that these data will serve as a resource for pediatric oncology drug development and guide rational clinical trial design for children with cancer.\n\nHighlightsO_LIMultiplatform genomic analysis defines landscape of 261 pediatric cancer patient derived xenograft (PDX) models\nC_LIO_LIPediatric patient derived xenografts faithfully recapitulate relapsed disease\nC_LIO_LIInferred TP53 pathway inactivation correlates with pediatric cancer copy number burden\nC_LIO_LISomatic mutational signatures predict impaired DNA repair across multiple histologies\nC_LI

genomics↗