Biology subjects

Heywood, W. E.

Publications and source records attributed to Heywood, W. E..

4 recordsLinked to original sources

bioRxiv2026

A novel pipeline for the validation of manganese chelators for the treatment of manganese overload

Manganese neurotoxicity, arising from environmental overexposure or inherited transporter disorders due to pathogenic variants in SLC30A10 and SLC39A14, leads to manganism, a debilitating Parkinsonian movement disorder. Alhtough chelation therapy can partially reverse neuropathology, current clinical practice relies on intravenous CaNa2EDTA, which is burdensome and poorly suited for long-term use. Consequently, there remains a significant unmet need for more effective, orally bioavailable chelators. This study aimed to establish and validate a pipeline for identifying and assessing novel ligands that attenuate manganese neurotoxicity and support preclinical translational development. Based on the structural features of manganese-based MRI contrast agents, we selected two chelators, N-picolyl-N,N',N'-trans-1,2-cyclohexylenediaminetriacetic acid (H3PyC3A) and ethylenediaminetetraacetic acid-benzothiazole aniline (H4EDTA-BTA), and their methyl ester derivatives, Me3PyC3A and Me4EDTA-BTA. These were evaluated in vivo using zebrafish (slc39a14U801/U801) and mouse (Slc30a10KO/KO) models of manganese overload. H3PyC3A and Me3PyC3A demonstrated greater manganese-mobilizing efficacy than CaNa2EDTA, improving locomotor behavior in slc39a14U801/U801 zebrafish. In Slc30a10KO/KO mice, intravenous administration confirmed selective in vivo chelation of excess manganese over physiological concentrations of zinc and copper. Although oral bioavailability was low (<1%), long-term oral administration of H3PyC3A modestly reduced liver and brain Mn accumulation, suggesting an added benefit of oral administration via gastrointestinal chelation. This integrated in vitro to in vivo pipeline provides a robust and scaleable approach for the development of next-generation Mn chelators. Slc39a14U801 loss-of-function zebrafish enable high throughput identification of candidate compounds while Slc30a10KO/KO mice offer a clinically relevant disease model for pharmacokinetic profiling and proof-of-concept validation.

pharmacology and toxicology↗

bioRxiv2025

Apolipoprotein E abundance is elevated in the brains of individuals with Down syndrome-Alzheimer's disease

Trisomy of chromosome 21, the cause of Down syndrome (DS), is the most commonly occurring genetic cause of Alzheimers disease (AD). Here, we compare the frontal cortex proteome of people with Down syndrome-Alzheimers disease (DSAD) to demographically matched cases of early-onset AD and healthy ageing controls. We find wide dysregulation of the proteome, beyond proteins encoded by chromosome 21, including an increase in the abundance of the key AD-associated protein, APOE, in people with DSAD compared to matched cases of AD. To understand the cell types that may contribute to changes in protein abundance, we undertook a matched single-nuclei RNA-sequencing study, which demonstrated that APOE expression was elevated in subtypes of astrocytes, endothelial cells and pericytes in DSAD. We further investigate how trisomy 21 may cause increased APOE. Increased abundance of APOE may impact the development of, or response to, AD pathology in the brain of people with DSAD, altering disease mechanisms with clinical implications. Overall, these data highlight that trisomy 21 alters both the transcriptome and proteome of people with DS in the context of AD, and that these differences should be considered when selecting therapeutic strategies for this vulnerable group of individuals who have high-risk of early-onset dementia.

neuroscience↗

bioRxiv2024

Multi-Omic Analysis Reveals Lipid Dysregulation Associated with Mitochondrial Dysfunction in Parkinson's Disease Brain

Parkinsons Disease (PD) is an increasingly prevalent condition within the aging population. PD can be attributed to rare genetic mutations, but most cases are sporadic where the gene-environment interactions are unknown/likely contributory. Age related dysregulation of the glycosphingolipid degradation pathway has been implicated in the development of PD, however, our understanding of how brain lipids vary across different regions of the brain, with age and in disease stages, remains limited. In this study we profiled several phospho- and sphingolipid classes in eight distinct regions of the human brain and investigated the association of lipids with a spatio-temporal pathology gradient, utilising PD samples from early, mid, and late stages of the disease. We performed high-precision tissue sampling in conjunction with targeted LC-MS/MS and applied this to post-mortem samples from PD and control subjects. The lipids were analysed for correlations with untargeted proteomics and mitochondrial activity data, in a multi-omics approach. We concluded that the different brain regions demonstrated their own distinct profiles and also found that several lipids were correlated with age. The strongest differences between PD and controls were identified in ganglioside, sphingomyelin and n-hexosylceramides. Sphingomyelin was also found to correlate with several proteins implicated in Parkinsons disease pathways. Mitochondrial activity was correlated with the levels of several lipids in the putamen region. Finally, we identified a gradient corresponding to Braaks disease spread across the brain regions, where the areas closer to the brainstem/substantia nigra showed alterations in PC, LPC and glycosphingolipids, while the cortical regions showed changes in glycosphingolipids, specifically gangliosides, HexCer and Hex2Cer. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=116 SRC="FIGDIR/small/604051v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@d4851eorg.highwire.dtl.DTLVardef@6f9d00org.highwire.dtl.DTLVardef@1ac9d7dorg.highwire.dtl.DTLVardef@197808e_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2023

The emergence of goblet inflammatory or ITGB6hi nasal progenitor cells determines age-associated SARS-CoV-2 pathogenesis

Children infected with SARS-CoV-2 rarely progress to respiratory failure, but the risk of mortality in infected people over 85 years of age remains high, despite vaccination and improving treatment options. Here, we take a comprehensive, multidisciplinary approach to investigate differences in the cellular landscape and function of paediatric (<11y), adult (30- 50y) and elderly (>70y) nasal epithelial cells experimentally infected with SARS-CoV-2. Our data reveal that nasal epithelial cell subtypes show different tropism to SARS-CoV-2, correlating with age, ACE2 and TMPRSS2 expression. Ciliated cells are a viral replication centre across all age groups, but a distinct goblet inflammatory subtype emerges in infected paediatric cultures, identifiable by high expression of interferon stimulated genes and truncated viral genomes. In contrast, infected elderly cultures show a proportional increase in ITGB6hi progenitors, which facilitate viral spread and are associated with dysfunctional epithelial repair pathways. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=155 SRC="FIGDIR/small/524211v2_ufig1.gif" ALT="Figure 1"> View larger version (61K): org.highwire.dtl.DTLVardef@dab12aorg.highwire.dtl.DTLVardef@1a57334org.highwire.dtl.DTLVardef@12e7983org.highwire.dtl.DTLVardef@2bbe6e_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗