Biology subjects

Davies, M.

Publications and source records attributed to Davies, M..

At least 19 recordsLinked to original sources

bioRxiv2026

Targeting skin ageing at the source: a novel cellular reprogramming approach using natural extract combinations

Cellular senescence is a driver of skin ageing that leads to structural deterioration and aesthetic changes. This study evaluated a novel senomorphic strategy, using synergistic combinations of natural small molecules to target RNA splicing regulation via upstream ERK/AKT signaling pathways. Nature-identical synthetic molecules, and corresponding extracts were assessed for cytotoxicity, impact on senescent cell load, proliferation, DNA damage load and SASP markers in naturally aged human primary skin cells. A topical, simple formulation was evaluated for impact on senescence and skin structure using 3D human ex vivo full-thickness skin explants exposed to 1.5 J/cm2 UVC irradiation. Combination of H. lupulus and G. biloba extracts produced a dose-dependent senomorphic impact of up to 45% in aged dermal fibroblasts and 10% in aged human primary keratinocytes (p [≤] 0.0001 & 0.001), without inducing cell proliferation. A 50% decrease in DNA damage load was also observed (p [≤] 0.0001). Qualitatively, the simple formulation mitigated UV-induced epidermal hyperplasia, restored collagen fiber organization, and reduced markers of senescence and inflammation. Targeting cellular senescence is an emerging traction point to address the root biological causes of skin ageing. Targeting the splicing dysregulation/senescence axis using combinations of natural plant extracts may provide a novel mode of action to reprogram senescent cells for repair and protection of skin structure and function.

cell biology↗

bioRxiv2026

Cell size overrides ganglion mother cell fate specification in Drosophila

The size of cells varies enormously in biology and how cell size and function are linked are fundamental questions. Asymmetrically dividing Drosophila neural stem cells, also called neuroblasts, produce a large neuroblast and a smaller ganglion mother cell (GMC) at each division. However, why GMCs need to be smaller than neuroblasts has largely remained unexplained. Here, we developed acute and reversible methods to alter daughter-cell size during a single neuroblast division while preserving cortical polarity and asymmetric inheritance of fate determinants. We identify atypical protein kinase C (aPKC) as a regulator of size asymmetry and show that transient and partial co-inhibition of aPKC and Rho kinase (Drok in Drosophila) generates daughters spanning a size range, including size-wise near-symmetric sibling cells while polarity is preserved. We find that above a certain size threshold daughter cells retain neuroblast-like properties despite inheriting GMC determinants: they divide repeatedly, exhibit neuroblast-like cell-cycle timing, and undergo size-wise asymmetric division. Smaller daughters below this threshold instead follow a GMC-like trajectory. Thus, in Drosophila type I neuroblasts, daughter-cell size can act as a regulator of lineage behaviour, overriding inherited fate cues in sufficiently large daughter cells.

developmental biology↗

bioRxiv2026

Establishment of an avian influenza surveillance program in Australia's largest river basin

To-date Australia has had mostly coastal occurrences in a small but growing number of species of high pathogenicity avian influenza (HPAI) H5N1 clade 2.3.4.4b. The potential impacts of expected spread are the focus of significant preparation activities. Here we report on early surveillance undertaken in 2025-26 in the Murray-Darling Basin, Australia's largest river system, which contains internationally important wetlands that support large multi-species aggregations of waterbirds vulnerable to mass mortality. We detected two low pathogenicity avian influenza (LPAI) viruses of Australian origin in wild waterbirds. Ongoing surveillance will aid in early detection and rapid response in the case of a major inland outbreak of H5N1.

microbiology↗

bioRxiv2026

Microbiota-sensitive glial and metabolic programs define a critical window in early postnatal brainstem development

Paediatric brain tumours are increasingly recognised as diseases of disrupted development, arising when lineage progression programs, that normally govern neural and glial maturation, become stalled or dysregulated. Diffuse midline glioma (DMG), a highly aggressive paediatric brainstem tumour, emerges during early childhood in the pons, a region undergoing rapid postnatal growth characterized by oligodendrocyte precursor cell (OPC) proliferation and differentiation. However, the environmental factors that shape these developmental trajectories remain poorly defined. Here, using germ-free and conventionally colonized mice, we investigated whether early-life microbiota influences transcriptional and metabolic programs in the developing brainstem during this critical developmental window. Bulk RNA sequencing revealed pronounced microbiota-associated transcriptional differences at postnatal day 2 (P2), but not at P8, identifying a temporally restricted period during which microbial colonization is associated with pathways linked to oligodendrocyte lineage progression, myelination, and neuroimmune signalling. Transcriptional analyses further identified altered expression of genes associated with CD11c microglia, a developmental microglial subtype implicated in regulating oligodendrocyte maturation. Untargeted metabolomic profiling revealed parallel microbiota-associated differences in pathways related to mitochondrial function, redox balance, and methyl-donor metabolism. Integrated multi-omics analyses identified coordinated networks linking glial lineage programs with metabolites involved in cellular metabolism and epigenetic regulation. Notably, several of these transcriptional and metabolic programs overlap with gene signatures reported in diffuse midline glioma, suggesting that microbiota-sensitive developmental pathways intersect with cellular states relevant to paediatric brainstem tumour biology.

neuroscience↗

bioRxiv2026

SHP2 binds directly to SOS1 to enable RAS activation

The protein-tyrosine phosphatase SHP2 (PTPN11) regulates growth factor- and cytokine-induced RAS/ERK MAP kinase (MAPK) pathway activation, and aberrant SHP2 function causes developmental disorders and cancer1-5. It is widely believed that the catalytic activity of SHP2 is essential for pathway activation1,4,6-8. This view has shaped our interpretation of how germline PTPN11 mutations cause Noonan Syndrome (NS) and NS with Multiple Lentigines (NS-ML)2,9 and how somatic mutations contribute to myeloproliferative neoplasms and solid tumors1. Here we identify a previously undetected, protein-tyrosine phosphatase (PTP) activity-independent mechanism that revises our understanding of how SHP2 promotes RAS/ERK activation. We find that certain mutations of the nucleophilic cysteine that abolish catalytic activity still promote RAS/ERK pathway activation in normal and neoplastic mammalian cells, zebrafish embryos, and mice. Structural studies show that the SHP2 PTP domain binds directly to the Son of Sevenless 1 (SOS1) Dbl homology (DH) domain. Proximity labeling and super-resolution microscopy demonstrate that SHP2/SOS1 interaction occurs in cells and facilitates SOS1 translocation to the plasma membrane to form clusters. Our results overturn decades of dogma on SHP2 regulation of the RAS/ERK pathway and provide new insights into the mechanism of action of disease-associated PTPN11 mutations.

Cancer Biology↗

bioRxiv2026

Ploidy shapes gemcitabine response through altered potency and delayed cell death

Aberrant tumor ploidy is a near-universal hallmark of cancer and increasingly recognized as a determinant of therapeutic response, but the mechanisms by which ploidy shapes sensitivity to specific cytotoxic agents remain unclear. Here, we investigated the relationship between ploidy and therapeutic response using pharmacogenomic reanalysis, isogenic cancer cell systems, live-cell imaging, intracellular pharmacokinetic/ pharmacodynamic (PK/PD) measurements, and mathematical modeling. Across public pharmacogenomic datasets, gemcitabine emerged as a low-ploidy-selective cytotoxic agent. In matched isogenic low- and high-ploidy cell systems, higher-ploidy cells were consistently less sensitive to gemcitabine across multiple lineages. Live-cell imaging and PK/PD measurements in near-diploid and near-tetraploid SUM-159 cells showed that both states formed intracellular dFdCTP, active form of gemcitabine; but, high-ploidy cells exhibited weaker and slower treatment responses, with delayed accumulation of cell death. To quantify these differences, we developed a delay-aware live/dead model driven by intracellular dFdCTP exposure. The model identified both reduced effective gemcitabine potency and a substantially longer delay from intracellular drug action to observed death in high-ploidy cells (17.5 hours in near-diploid cells versus 42.5 hours in near-tetraploid cells). Interpreting these fitted quantities alongside checkpoint signaling and metabolomic profiling suggests that high-ploidy cells convert intracellular gemcitabine exposure less efficiently into replication-stress signaling, nucleotide-metabolic disruption, and cytotoxic commitment. Together, these results establish ploidy as a determinant of both the magnitude and timing of gemcitabine response and provide a quantitative framework for linking intracellular drug exposure to delayed cytotoxic outcomes across ploidy states.

cancer biology↗

bioRxiv2026

Mutant KRAS promotes NF-kB driven CCL20 chemokine expression in pancreatic ductal adenocarcinoma

The chemokine CCL20 is implicated in inflammation and cancer but has proven challenging to target therapeutically. In this study, we precisely define what cells produce CCL20 in pancreatic inflammation and cancer. Through analysis of single cell RNA data, mutation and copy number signatures, gene methylation, and in vitro studies, we show that CCL20 and other NF-{kappa}B driven chemokine production is largely dependent on oncogenic KRAS in the malignant pancreas. Blockade of CCL20-CCR6 signaling in vivo using a novel partial agonist inhibitor, CCL20LD, increased recruitment of antigen presenting cells without significantly impinging tumor growth. Lastly, resistance to pan-RAS or allele-specific KRAS inhibitors decreased CCL20-dependent immune recruitment in culture. These results suggest that oncogenic KRAS activates NF-{kappa}B signaling in human pancreas cancer, resulting in pharmacologically reversible changes to chemokine production that may participate in immune suppression or immune evasion within the pancreas cancer microenvironment.

cancer biology↗

bioRxiv2026

Attenuated interferon signalling in alveolar epithelium limits resistance to Streptococcus pyogenes

The upper respiratory tract is a primary niche for Streptococcus pyogenes colonisation and disease. Lower respiratory tract infection (pneumonia) is the most common invasive S. pyogenes syndrome. Studies have not previously examined how epithelial cells, from the airway to the alveolus, respond to S. pyogenes infection. Here, we established a scalable human in vitro model by differentiating induced pluripotent stem cells (iPSCs) into mature pseudostratified airway epithelium or alveolar type 2 epithelial cells, cultured at air-liquid interface and infected with S. pyogenes (M1UK and M75 strains). Both strains attached to iPSC-derived lung epithelial cells, with significantly greater adherence to the airway epithelium by M75 compared to M1UK. Moreover, invasion by both S. pyogenes strains of alveolar epithelial cells was greater than for the airway epithelium. Dynamic S. pyogenes gene expression changes were evident between 6 and 24 hours after infection, which was influenced by the infected cell type; however, virulence genes were not significantly altered. While infection of the airway epithelium induced rapid and dynamic inflammatory signalling, the alveolar epithelium demonstrated augmented cell death and mounted a transcriptional pro-inflammatory and proliferative response that was uncoupled from cytokine secretion. The airway epithelium model exhibited consistently higher baseline type I interferon (IFN) signalling than the alveolar epithelium. Invasion by S. pyogenes and inflammation was significantly reduced in IFN-{beta}-treated alveolar epithelial cells. In summary, we have established the first model of S. pyogenes infection in physiologically relevant airway and alveolar epithelial cells. Our findings suggest that host responses to infection are influenced by lung compartment, the S. pyogenes strain type, and infection timepoint, highlighting context-specific pathways that could be leveraged therapeutically.

microbiology↗

bioRxiv2025

AEBP2-Directed H3K27me2 Defines a Specific Vulnerability in EZH2-mutant Lymphoma

The catalytic subunit of Polycomb Repressive Complex 2 (PRC2), EZH2, is recurrently mutated in 25% of diffuse large B-cell lymphomas (DLBCL), causing increased H3K27me3 and decreased H3K27me2 levels. EZH2 inhibitors provide clinical benefit, but resistance frequently develops, highlighting the need for alternative therapeutic targets. Here, we identify the PRC2 accessory protein AEBP2 as a specific genetic dependency in EZH2-mutant DLBCL. While AEBP2 acts through PRC2, its essential role is surprisingly independent of canonical H3K27me3-mediated gene silencing. Instead, AEBP2 functions within a PRC2.2 complex lacking JARID2, using its zinc-finger domains to sample intergenic chromatin to sustain H3K27me2. Notably, loss of AEBP2 or NSD2 caused contrasting changes in intergenic H3K27me2 levels, driving sensitivity or resistance to PRC2 inhibitors, respectively. Our findings identify AEBP2-PRC2.2-maintained intergenic H3K27me2 as a therapeutic vulnerability in EZH2-mutant DLBCL and highlight dysregulated H3K27me2 as an underappreciated form of PRC2 dysfunction in cancer, with important therapeutic implications.

cancer biology↗

bioRxiv2025

Immunogenicity and Efficacy of Digitally Immune Optimised H1N1 Vaccine Candidates in Swine and Murine Animal Models

Influenza A virus (IAV) zoonotic transmission and constant evolution in multiple species heightens the risk of emerging novel strains at the human-animal interface. Composite antigens including hemagglutinin (HA), neuraminidase (NA), and matrix-2 (M2) proteins were computationally designed to maximize the breadth of the immune response elicited to human seasonal, pandemic, and zoonotic H1N1 IAVs. Mouse hyperimmune serum raised against these antigens demonstrated broad H1 neutralization and N1 inhibition activity. To enhance immunogenicity, the antigens were combined as a single DNA expression construct (DVX-H1N1). Studies in the well-recognized swine model for human influenza demonstrated that DVX-H1N1 immunization induced broad, neutralizing antibody responses and markedly reduced nasal shedding of viral RNA following challenge with 1A.3.3.2 subclade strain A/swine/England/1353/2009 (H1N1). An effective immune response and reduction in virus shedding was observed in pigs immunized with a whole inactivated virus (WIV) vaccine homologous to the challenge strain but not with a human-origin seasonal WIV vaccine. Overall, we demonstrated broad immunogenicity and efficacy of the DVX-H1N1 vaccine candidate, benchmarked against relevant IAV H1N1 strains in vitro and in vivo in mice and pigs. IMPORTANCEThe zoonotic potential of swine-origin IAVs is a recognized global health threat. Vaccination remains the most effective intervention against influenza; protecting at the population level by preventing nasal shedding and transmission, but also in individuals by limiting clinical disease, particularly by reducing the severity of lung infection. The World Health Organization (WHO) spearheads biannual surveillance efforts to review evolving virus strains and vaccine antigens at Vaccine Candidate Meetings (VCM) to recommend strain updates for the human seasonal influenza vaccine and for pandemic preparedness purposes. However, the strain selection approach is complex and efficaciousness of seasonal influenza vaccines still varies significantly based on the accurate matching of the predicted strains in circulation with the manufactured vaccine antigens. This emphasizes the need for next-generation influenza vaccines that improve the breadth and longevity of immunity. We describe a computationally optimized DNA vaccine with broad immunogenicity and robust efficacy in the pig model.

immunology↗

bioRxiv2025

A novel resistant starch supplement induced significant weight loss in obese/overweight dogs

ObjectivesTo evaluate whether a resistant-starch containing supplement administered for 30 days would induce significant weight loss and lower body condition score (BCS) in overweight/obese dogs, compared to placebo. Methods21 home-based dogs in Norway completed the study. Study population included 15 breeds of which n=11 were male and n=10 female, ages ranged from 3 - 10 years (Mean 6.7). Weight and BCS were recorded at baseline (Day 0) and after 30 days feeding supplement A ( active ingredient). Subsequently, after a 5-day wash-out period with no supplement, all dogs received supplement B ( placebo) for a further 30 days, when they were re-weighed and BCS scored. Owners and the veterinarian overseeing the study were blinded to content of supplements. ResultsThe resistant-starch-containing supplement led to statistically significant weight loss (0.45 {+/-} 0.57 kg, mean {+/-} 1SD; P = 0.002) with 17 of 21 dogs (77%) losing weight. A 0.5 unit reduction in BCS was noted (P = 0.009). Dogs lost some weight on placebo, but BCS did not change. Clinical significanceThis novel supplement containing resistant-starch, beta-glucan, alpha-lipoic acid and probiotic can be used to induce weight loss in overweight/obese dogs.

animal behavior and cognition↗

bioRxiv2025

Developing an approach to list bryophytes of conservation interests for England's Local Nature Recovery Strategies

Biodiversity is globally declining, and the United Kingdom (UK) recognised as one of the most nature-depleted countries. With an aim to restore ecosystems, the UK has initiated a policy of Local Nature Recovery Strategies (LNRS), to be published for 48 areas across England. We devised and applied a workflow using open access data to produce preliminary lists of bryophytes of conservation interest for each LNRS area. Our objectives include: (i) to ascertain which LNRS area match the current recording scheme based on Watsonian vice-counties; (ii) to produce data-driven draft lists for each LNRS area, (iii) to compare this list in the Tees Valley area with a species list derived from expert knowledge. Using an inclusion threshold at 90% of surface area, we found that 20 out of the 48 LNRS areas are compatible with the vice-county-based scheme. We determine that LNRS areas included on average 9.3 (+/- 6.9) species threatened by extinction, a supplementary 3.6 (+/- 3.4) species near threatened and, adding nationally rare or scarce species, a total of 66.3 (+/- 35.1) species. A case study based on the Tees Valley revealed an overall good match between data and expert driven species lists, despite discrepancies relating to geographical attributions near boundaries and additional species solely selected by expert opinion. It is anticipated that the preliminary lists produced could save valuable time to local experts when working towards LNRS bryophyte lists, and that the approach developed will be relevant to other organism groups, supporting effectively LNRSs across England.

ecology↗

bioRxiv2025

The UAP56 mRNA Export Factor is Required for Dendrite and Synapse Pruning via Actin Regulation in Drosophila

Neurite and synapse pruning are conserved mechanisms that adapt neuronal circuitry to different developmental stages. Drosophila sensory c4da neurons prune their larval dendrites and their presynaptic terminals during metamorphosis using a gene expression programme that is induced by the steroid hormone ecdysone and involves posttranscriptional regulation pathways. Here we show that loss of the helicase UAP56, an important mediator of nuclear mRNA export, causes strong dendrite and presynapse pruning defects. Loss of UAP56 is linked to actin regulation, as it causes defects in the expression of the actin severing enzyme Mical during dendrite pruning, and actin accumulation at presynapses, where cofilin is required for pruning. Our findings suggest specificity in mRNA export pathways and identify a role for actin disassembly during presynapse pruning.

neuroscience↗

bioRxiv2025

Orthogonal chemical genomics approaches reveal genomic targets for increasing anaerobic chemical tolerance in Zymomonas mobilis

Genetically-engineered microbes have the potential to increase efficiency in the bioeconomy by overcoming growth-limiting production stress. Screens of gene perturbation libraries against production stressors can identify high-value engineering targets, but follow-up experiments needed to guard against false positives are slow and resource-intensive. In principle, the use of orthogonal gene perturbation approaches could increase recovery of true positives over false positives because the strengths of one technique compensate for the weaknesses of the other, but, in practice, two parallel screens are rarely performed at the genome-scale. Here, we screen genome-scale CRISPRi (CRISPR interference) knockdown and TnSeq (transposon insertion sequencing) libraries of the bioenergy-relevant Alphaproteobacterium, Zymomonas mobilis, against growth inhibitors commonly found in deconstructed plant material. Integrating data from the two gene perturbation techniques, we established an approach for defining engineering targets with high specificity. This allowed us to identify all known genes in the cytochrome bc1 and cytochrome c synthesis pathway as potential targets for engineering resistance to phenolic acids under anaerobic conditions, a subset of which we validated using precise gene deletions. Strikingly, this finding is specific to the cytochrome bc1 and cytochrome c pathway and does not extend to other branches of the electron transport chain. We further show that exposure of Z. mobilis to ferulic acid causes substantial remodeling of the cell envelope proteome, as well as the downregulation of TonB-dependent transporters. Our work provides a generalizable strategy for identifying high-value engineering targets from gene perturbation screens that is broadly applicable. IMPORTANCEEngineering microorganisms to tolerate harsh production conditions stands to increase bioproduct yields of engineered microbes. In this study, we systematically identified Z. mobilis genes that confer resistance or susceptibility to chemical stressors found in deconstructed plant material. We used complementary genetic techniques to cross-validate these genes at scale, providing a widely applicable method for precisely identifying genetic alterations that increase chemical resilience. We discovered genetic modifications that improve anaerobic growth of Z. mobilis in the presence of inhibitory chemicals found in renewable plant-based feedstocks. These results have implications in engineering robust production strains to support efficient and resilient bioproduction. Our methodologies can be broadly applied to understand microbial responses to chemicals across systems, paving the way for developments in biomanufacturing, therapeutics, and agriculture.

genomics↗

bioRxiv2025

Spectraplakin cooperates with noncentrosomal microtubule regulators to orient dendritic microtubules in Drosophila

The differential microtubule organization in axons and dendrites underlies neuronal polarity and developmental processes like neurite pruning. How neurons achieve their specific microtubule organization during development is an area of active research, and it has been especially hard to explain how dendritic microtubules are oriented with their plus ends towards the soma. Transient microtubule nucleation from tips of early growing dendrites has been detected in some systems and would explain how orientation is set up. In a survey for cytoskeletal regulators involved in dendrite pruning and microtubule organization in Drosophila, we found the spectraplakin Short stop (Shot), an actin/microtubule crosslinker. Loss of Shot causes microtubule orientation defects already during early dendrite development, when Shot is transiently recruited to tips of growing dendrites via its actin binding domain. Genetic and functional evidence suggest that Shots primary function in this process is to locally stabilize microtubules. We also provide evidence for a developmentally transient microtubule nucleation mechanism. Our data highlight the importance of transient and localized microtubule regulation for dendritic microtubule organization.

developmental biology↗

bioRxiv2025

Delaying Cancer Progression by Integrating Toxicity Constraints in a Model of Adaptive Therapy

Cancer therapies often fail when intolerable toxicity or drug-resistant cancer cells undermine otherwise effective treatment strategies. Over the past decade, adaptive therapy has emerged as a promising approach to postpone emergence of resistance by altering dose timing based on tumor burden thresholds. Despite encouraging results, these protocols often overlook the crucial role of toxicity-induced treatment breaks, which may permit tumor regrowth. Herein, we explore the following question: would incorporating toxicity feedback improve or hinder the efficacy of adaptive therapy? To address this question, we propose a mathematical framework for incorporating toxic feedback into treatment design. We find that the degree of competition between sensitive and resistant populations, along with the growth rate of resistant cells, critically modulates the impact of toxicity feedback on time to progression. Further, our model identifies circumstances where strategic treatment breaks, which may be based on either tumor size or toxicity, can mitigate overtreatment and extend time to progression, both at the baseline parameterization and across a heterogeneous virtual population. Taken together, these findings highlight the importance of integrating toxicity considerations into the design of adaptive therapy.

systems biology↗

bioRxiv2025

Viscoelastic HyA Hydrogel Promotes Recovery of Muscle Quality and Vascularization in a Murine Model of Delayed Rotator Cuff Repair

Rotator cuff tears are among the most common musculotendinous injuries with high risk of permanent functional disability. Following surgical repair, sub-optimal patient outcomes are directly correlated with poor muscle quality; namely, injury site fatty infiltration (FI), fibrosis, and muscle atrophy. Muscle resident fibro-adipogenic progenitor cells (FAPs) have been identified as key regulators of post-injury skeletal muscle regeneration and repair by maintaining a promyogenic environment. In this work, human-derived FAPs (hFAPs) were encapsulated into hyaluronic acid (HyA)-based hydrogels functionalized with bsp-RGD(15) cell adhesion peptide, heparin, and a matrix metalloproteinase (MMP)-cleavable crosslinker. Hydrogel-encapsulated hFAPs increased expression of the promyogenic marker UCP1 and production of the anti-inflammatory cytokine IL-10, while downregulating the expression of the fibrotic marker SMA over time. A murine model of unilateral rotator cuff transection, denervation, and delayed repair was treated with the HyA hydrogel or PBS and compared to a contralateral, non-injured control limb. Muscle histology 6 weeks post-repair revealed that the hydrogel reduced fibrosis, FI, and muscle atrophy while supporting vascularization of the injured tissue region. Collectively, these results suggest that the hydrogel alone can promote muscle regeneration in a clinically relevant delayed repair model of rotator cuff tear, which we hypothesize is due to controlled FAP differentiation into promyogenic lineages.

bioengineering↗

bioRxiv2024

GLP-1 receptor agonism ameliorates Parkinsons disease through modulation of neuronal insulin signalling and glial suppression

Neuronal insulin resistance is linked to the pathogenesis of Parkinsons disease through unclear, but potentially targetable, mechanisms. We delineated neuronal and glial mechanisms of insulin resistance and glucagon-like 1 peptide (GLP-1) receptor agonism in human iPSC models of synucleinopathy, and corroborated our findings in patient samples from a Phase 2 trial of a GLP-1R agonist in Parkinsons (NCT01971242). Human iPSC models of synucleinopathy exhibit neuronal insulin resistance and dysfunctional insulin signalling, which is associated with inhibition of the neuroprotective Akt pathways, and increased expression of the MAPK-associated p38 and JNK stress pathways. Ultimately, this imbalance is associated with cellular stress, impaired proteostasis, accumulation of -synuclein, and neuronal loss. The GLP-1R agonist exenatide led to restoration of insulin signalling, associated with restoration of Akt signalling and suppression of the MAPK pathways in neurons. GLP-1R agonism reverses the neuronal toxicity associated with the synucleinopathy, through reduction of oxidative stress, improved mitochondrial and lysosomal function, reduced aggregation of -synuclein, and enhanced neuronal viability. GLP-1R agonism further suppresses synuclein induced inflammatory states in glia, leading to neuroprotection through non cell autonomous effects. In the exenatide-PD2 clinical trial, exenatide treatment was associated with clinical improvement in individuals with higher baseline MAPK expression (and thus insulin resistance). Exenatide treatment led to a reduction of -synuclein aggregates, and a reduction in inflammatory cytokine IL-6. Taken together, our patient platform defines the mechanisms of GLP-1R action in neurons and astrocytes, identifies the population likely to benefit from GLP-1R agonism, and highlights the utility of GLP-1R agonism as a disease modifying strategy in synucleinopathies.

neuroscience↗