Biology subjects

Fenton, T.

Publications and source records attributed to Fenton, T..

4 recordsLinked to original sources

bioRxiv2025

A non-vesicular Argonaute protein is transmitted from nematode to mouse and is important for parasite survival

Argonautes are ancient proteins with well-characterised functions in cell-autonomous gene regulation and genome defense but less clear roles in non-cell-autonomous processes. Extracellular Argonautes have been reported across plants, animals and protozoa yet their biochemical and functional properties remain elusive. Here we demonstrate that an extracellular Argonaute (exWAGO) released by the rodent-infective parasitic nematode Heligmosomoides bakeri is detectable inside mouse cells during the natural infection. We further show that exWAGO is released from H.bakeri in both vesicular and non-vesicular forms that have different resistances to proteolysis, different accessibilities to antibodies and associate with different subsets of secondary siRNAs. Using recombinant exWAGO protein we demonstrate that non-vesicular exWAGO is directly internalised by mouse cells in vitro and that immunisation of mice with exWAGO confers partial protection against subsequent H. bakeri infection and generates antibodies that block exWAGO uptake into cells. Finally, we show that properties of exWAGO are conserved across Clade V nematodes that infect humans and livestock. Together this work expands the context in which Argonautes function and illuminates an RNA-binding protein as a vaccine target for parasitic nematodes.

molecular biology↗

bioRxiv2024

Differential roles of NaV1.2 and NaV1.6 in neocortical pyramidal cell excitability

Mature neocortical pyramidal cells functionally express two sodium channel (NaV) isoforms: NaV1.2 and NaV1.6. These isoforms are differentially localized to pyramidal cell compartments, and as such are thought to contribute to different aspects of neuronal excitability. But determining their precise roles in pyramidal cell excitability has been hampered by a lack of tools that allow for selective, acute block of each isoform individually. Here, we leveraged aryl sulfonamide-based molecule (ASC) inhibitors of NaV channels that exhibit state-dependent block of both NaV1.2 and NaV1.6, along with knock-in mice with changes in NaV1.2 or NaV1.6 structure that prevents ASC binding. This allowed for acute, potent, and reversible block of individual isoforms that permitted dissection of the unique contributions of NaV1.2 and NaV1.6 in pyramidal cell excitability. Remarkably, block of each isoform had contrasting--and in some situations, opposing--effects on neuronal action potential output, with NaV1.6 block decreasing and NaV1.2 block increasing output. Thus, NaV isoforms have unique roles in regulating different aspects of pyramidal cell excitability, and our work may help guide development of therapeutics designed to temper hyperexcitability through selective NaV isoform blockade.

neuroscience↗

bioRxiv2023

Hyperexcitability and translational phenotypes in a preclinical model of SYNGAP1 mutations

SYNGAP1 is a critical gene for neuronal development, synaptic structure, and function. Although rare, the disruption of SYNGAP1 directly causes a genetically identifiable neurodevelopmental disorder (NDD) called SYNGAP1-related intellectual disability. Without functional SynGAP1 protein, patients present with intellectual disability, motor impairments, and epilepsy. Previous work using mouse models with a variety of germline and conditional mutations has helped delineate SynGAP1s critical roles in neuronal structure and function, as well as key biochemical signaling pathways essential to synapse integrity. Homozygous loss of SYNGAP1 is embryonically lethal. Heterozygous mutations of SynGAP1 result in a broad range of phenotypes including increased locomotor activity, impaired working spatial memory, impaired cued fear memory, and increased stereotypic behavior. Our in vivo functional data, using the original germline mutation mouse line from the Huganir laboratory, corroborated robust hyperactivity and learning and memory deficits. Here, we describe impairments in the translational biomarker domain of sleep, characterized using neurophysiological data collected with wireless telemetric electroencephalography (EEG). We discovered Syngap1+/- mice exhibited elevated spike trains in both number and duration, in addition to elevated power, most notably in the delta power band. Primary neurons from Syngap1+/- mice displayed increased network firing activity, greater spikes per burst, and shorter inter-burst intervals between peaks using high density micro-electrode arrays (HD-MEA). This work is translational, innovative, and highly significant as it outlines functional impairments in Syngap1 mutant mice. Simultaneously, the work utilized untethered, wireless neurophysiology that can discover potential biomarkers of Syngap1R-ID, for clinical trials, as it has done with other NDDs. Our work is substantial forward progress toward translational work for SynGAP1R-ID as it bridges in-vitro electrophysiological neuronal activity and function with in vivo neurophysiological brain activity and function. These data elucidate multiple quantitative, translational biomarkers in vivo and in vitro for the development of treatments for SYNGAP1-related intellectual disability.

neuroscience↗

bioRxiv2018

Pan-cancer deconvolution of cellular composition identifies molecular correlates of antitumour immunity and checkpoint blockade response

The nature and extent of immune cell infiltration into solid tumours are key determinants of therapeutic response. Here, using a novel DNA methylation-based approach to tumour cell fraction deconvolution, we report the integrated analysis of tumour composition and genomics across a wide spectrum of solid cancers. Initially studying head and neck squamous cell carcinoma, we identify two distinct tumour subgroups: immune hot and immune cold, which display differing prognosis, mutation burden, cytokine signalling, cytolytic activity, and oncogenic driver events. We demonstrate the existence of such tumour subgroups pan-cancer, link clonal-neoantigen burden to hot tumours, and show that transcriptional signatures of hot tumours are selectively engaged in immunotherapy responders. We also find that treatment-naive hot tumours are markedly enriched for known immune-resistance genomic alterations and define a catalogue of novel and known mediators of active antitumour immunity, deriving biomarkers and potential targets for precision immunotherapy.

cancer biology↗