Biology subjects

Elmasri, M.

Publications and source records attributed to Elmasri, M..

3 recordsLinked to original sources

bioRxiv2026

Genetic or pharmacological disruption of the MSH3 Y245/K246 IDL binding pocket slows CAG repeat expansion

Recent genetic studies have shown somatic expansion of the CAG repeat is the key process driving Huntingtons disease (HD) pathogenesis. Recognition of insertion deletion loops (IDLs), lesions prone to form within the CAG repeat, by Muts{beta} (MSH3/MSH2) is thought to be the primary event in the expansion process. This starts a cascade that leads to error prone repair and incorporation of additional CAG units into the repeat. In vitro data shows MSH3 binds IDLs through a DNA binding pocket formed by MSH3 residues Y245/K246. In this study, we investigated the significance of this DNA binding motif in CAG repeat expansion using cell lines harboring long, unstable HTT CAG repeats. Genetic disruption of the MSH3 Y245/K246 motif significantly reduced DNA interaction, exhibited MMR deficiency in a frameshift mutator assay and abrogated repeat expansion in a U2OS cell line expressing mutant HTT exon 1. Pharmacological blockade of this site using a small molecule targeting the DNA binding pocket similarly reduced DNA binding and repeat expansion in a U2OS cell line. Crucially, this molecule also slowed CAG repeat expansion in medium spiny neurons derived from HD patient-iPSCs. Targeting of the MSH3 IDL binding pocket may represent a possible therapeutic strategy.

neuroscience↗

bioRxiv2020

Common synaptic phenotypes arising from diverse mutations in the human NMDA receptor subunit GluN2A

Dominant mutations in the human gene GRIN2A, encoding NMDA receptor (NMDAR) subunit GluN2A, make a significant and growing contribution to the catalogue of published single-gene epilepsies. Understanding the disease mechanism in these epilepsy patients is complicated by the surprising diversity of effects that the mutations have on NMDARs. We have examined the cell-autonomous effect of five GluN2A mutations, 3 loss-of-function and 2 gain-of-function, on evoked NMDAR-mediated synaptic currents (NMDA-EPSCs) in CA1 pyramidal neurons in cultured hippocampal slices. Despite the mutants differing in their functional incorporation at synapses, prolonged NMDA-EPSC current decays (with only marginal changes in charge transfer) were a common effect for both gain- and loss-of-function mutants. Modelling NMDA-EPSCs with mutant properties in a CA1 neuron revealed that the effect of GRIN2A mutations can lead to abnormal temporal integration and spine calcium dynamics during trains of concerted synaptic activity. Investigations beyond establishing the molecular defects of GluN2A mutants are much needed to understand their impact on synaptic transmission.

neuroscience↗

bioRxiv2020

Predicting missing links in global host-parasite networks

O_LIParasites that infect multiple species cause major health burdens globally, but for many, the full suite of susceptible hosts is unknown. Predicting undocumented host-parasite associations will help expand knowledge of parasite host specificities, promote the development of theory in disease ecology and evolution, and support surveillance of multi-host infectious diseases. Analysis of global species interaction networks allows for leveraging of information across taxa, but link prediction at this scale is often limited by extreme network sparsity, and lack of comparable trait data across species. C_LIO_LIHere we use recently developed methods to predict missing links in global mammal-parasite networks using readily available data: network properties and evolutionary relationships among hosts. We demonstrate how these link predictions can efficiently guide the collection of species interaction data and increase the completeness of global species interaction networks. C_LIO_LIWe amalgamate a global mammal host-parasite interaction network (>29,000 interactions) and apply a hierarchical Bayesian approach for link prediction that leverages information on network structure and scaled phylogenetic distances among hosts. We use these predictions to guide targeted literature searches of the most likely yet undocumented interactions, and identify empirical evidence supporting many of the top "missing" links. C_LIO_LIWe find that link prediction in global host-parasite networks can accurately predict parasites of humans, domesticated animals, and endangered wildlife, representing a combination of published interactions missing from existing global databases, and potential but currently undocumented associations. C_LIO_LIOur study provides further insight into the use of phylogenies for predicting host-parasite interactions, and highlights the utility of iterated prediction and targeted search to efficiently guide the collection of host-parasite interaction. These data are critical for understanding the evolution of host specificity, and may be used to support disease surveillance through a process of predicting missing links, and targeting research towards the most likely undocumented interactions. C_LI

ecology↗