Biology subjects

Mahon, C. S.

Publications and source records attributed to Mahon, C. S..

3 recordsLinked to original sources

bioRxiv2026

Detecting transcriptional responses and comparing the virulence of Pseudomonas aeruginosa cystic fibrosis isolates in a mung bean model

A mung bean infection model has previously been shown to differentiate between non-virulent and virulent Pseudomonas aeruginosa bacteria. However, it remains unclear how plant and bacteria adjust their gene expression during infection and whether the mung bean model can be used to compare the virulence of clinical cystic fibrosis (CF) P. aeruginosa lung isolates. Here, we first explored temporal transcriptomics of P. aeruginosa PAO1 and mung bean during an infection. We found that bacterial gene expression followed temporal changes, with an increase in the expression of O-antigen biosynthetic genes, chemotaxis, phosphate intake and phenazine production. Mung bean responded by upregulating genes associated with defence mechanisms and downregulating genes involved in the plant development. From the PAO1 perspective, the core-transcriptomic responses in the mung bean were similar to its responses previously observed in wound and excision and in in vitro media and sputum models, while differed from those observed in the bronchial cell model. Furthermore, we used the mung bean to assess the virulence of 119 clinical P. aeruginosa CF strains originating from the Copenhagen CF clinic. By quantifying bacterial virulence as a reduction in root and shoot growth and weight of the seeds, we found that CF strains isolated at later compared to early stages of lung infections showed higher virulence. This difference corresponded with the higher number of immune modulation-associated virulence genes and lower number of motility and effector genes, present in the genomes of late compared to early isolated CF strains. IMPORTANCEOur results demonstrate that based on PAO1 transcriptional profile, the mung bean model is similar to in vitro and wound infection models but differs from cell and bronchial models. Moreover, the mung bean model can detect virulence differences between clinical P. aeruginosa CF strains, making it a potentially useful high-throughput in vivo model for bacterial virulence screening.

microbiology↗

bioRxiv2025

A Common PD-Risk GBA1 Variant Disrupts LIMP2 Interaction, Impairs Glucocerebrosidase Function, and Drives Lysosomal and Mitochondrial Dysfunction

Variants in GBA1 cause Gaucher disease (GD), a lysosomal storage disorder, and represent the most common genetic risk factor for Parkinsons disease (PD). While some GBA1 variants are associated with both GD and PD, several coding mutations, including E326K, specifically confer risk for developing PD. It is established that GD-linked variants in {beta}-glucocerebrosidase (GCase), the enzyme encoded by GBA1, are loss-of-function, but it remains unclear whether variants solely associated with PD similarly reduce GCase activity. The mechanisms by which some of these variants impact GCase activity and PD-associated pathways, including lysosomal and mitochondrial function, are also poorly defined. Here, we show that the PD-linked E326K variant significantly reduces lysosomal GCase activity by impairing its delivery to lysosomes via altered interactions with its receptor, LIMP2. Biophysical and structural characterization of this variant, both alone and in complex with LIMP2, reveals a dimeric organization that appears to result from the loss of a key salt bridge between E326 and R329. Restoration of this salt bridge through the introduction of a negatively charged side chain at position 329 promotes monomeric organization and interaction with LIMP2 in cells. GBA1-p.E326K cell models show greater deficits in PD-linked pathways compared to more severe loss of GCase function, including secondary lysosomal lipid storage and mitochondrial dysfunction. We confirm the E326K variant impacts GCase pathway activity in relevant CNS cell types, including iPSC-derived microglia, and in biofluids from heterozygous GBA1-p.E326K variant carriers. Together, our data provide key insights into the nature of GCase dysfunction in GBA1-PD and can inform the development of GCase-targeted therapeutic strategies to treat PD.

cell biology↗

bioRxiv2021

Molecular architecture determines brain delivery of a transferrin-receptor targeted lysosomal enzyme

Delivery of biotherapeutics across the blood-brain barrier (BBB) is a challenge. Many approaches fuse biotherapeutics to platforms that bind the transferrin receptor (TfR), a brain endothelial cell target, to facilitate receptor-mediated transcytosis across the BBB. Here, we characterized the pharmacological behavior of two distinct TfR-targeted platforms fused to iduronate 2-sulfatase (IDS), a lysosomal enzyme deficient in mucopolysaccharidosis type II (MPS II), and compared the relative brain exposures and functional activities of both approaches in mouse models. IDS fused to a moderate-affinity, monovalent TfR binding enzyme transport vehicle (ETV:IDS) resulted in widespread brain exposure, internalization by parenchymal cells, and significant substrate reduction in the CNS of an MPS II mouse model. In contrast, IDS fused to a standard high-affinity bivalent antibody (IgG:IDS) resulted in lower brain uptake, limited biodistribution beyond brain endothelial cells, and reduced brain substrate reduction. These results highlight important features likely to impact the clinical development of TfR-targeting platforms in MPS II and potentially other CNS diseases. SummaryBrain delivery, biodistribution and pharmacodynamics of a lysosomal enzyme fused to a moderate-affinity transferrin receptor-directed blood-brain barrier enzyme transport vehicle are superior to a traditional high-affinity anti-TfR monoclonal antibody fusion.

neuroscience↗