Biology subjects

Blunskyte-Hendley, M.

Publications and source records attributed to Blunskyte-Hendley, M..

4 recordsLinked to original sources

bioRxiv2026

The adaptor protein DAB2 cell-autonomously links APOE with disease-associated microglia (DAM)/TREM2 state dysregulation associated with Alzheimer's disease

The neuron-secreted Reelin (RELN) protein and its adaptor DAB1 modify Alzheimer's disease (AD) risk through genetic interaction with APOE4. While RELN and APOE4 exert antagonistic effects on amyloid and Tau pathology in mice, how risk is conferred in the human brain remains unclear. The related adaptor DAB2 endocytoses RELN/APOE receptors and, via LRP8, modulates non-canonical pro-inflammatory signalling in non-neuronal cells. We hypothesised that RELN and APOE signalling directly influence microglial function to modify AD risk. Integrating human brain transcriptomics, a Reln-deficient mouse, and DAB1/DAB2 knock-down in APOE isogenic iPSC-microglia, we found that microglial DAB1/DAB2 pathways were dynamically regulated across the lifespan, with DAB2 dysregulated with increasing amyloid pathology. DAB2 transcriptional networks correlated with disease- and lipid- associated microglial states (DAM/LDAM) linked to networks expressing dementia-risk loci (TREM2, GRN, ACE, SORL1) and associated with endolysosomal and lipid-handling pathways. DAB2- knockdown cell-autonomously shifted microglia away from gene networks enriched in DAM/TREM2 states and towards pro-inflammatory cytokine-responsive states and TNFNF{kappa}B pathways. APOE4/E4 microglia showed elevated APOE and reduced DAB1pY232 under inflammatory stress, and blunted DAB2-knockdown transcriptomic responses, consistent with pathway-level genetic interaction. In vivo, RELN-deficiency reduced microglial ramification and increased CD68. These findings identify DAB2 as a regulator of microglial state transitions and a modifier of dementia-risk networks linking APOE genotype to inflammatory, phagocytic and amyloid-beta clearance pathways relevant to AD.

neuroscience↗

bioRxiv2026

Parental care is a genetic capacitor

Parental care is widespread across the animal kingdom and plays a critical role in offspring development. Yet, its broader genetic and evolutionary impacts remain underexplored. Here, using the biparental burying beetle Nicrophorus vespilloides as a model, we show that parental care acts as a genetic capacitor: it allows genetic variation to accumulate while care is present and releases it when care is disrupted. By experimentally manipulating care, we demonstrate that parental care suppresses genetic variation associated with offspring body size, which is released when care is lost. To investigate the underlying molecular mechanisms, we generate a chromosome-scale genome assembly for N. vespilloides, alongside a single-nucleus gene expression atlas and epigenomic datasets from larvae reared with and without parental care. We find that the loss of parental care induces molecular stress, disrupting the expression of the protein chaperone Hsp83, which is a well-known molecular capacitor, alongside other putative mRNA chaperones. Moreover, our results suggest that parental care buffers development by maintaining an open, responsive chromatin landscape and redundant gene regulatory interactions. Overall, our work reveals that parental care shapes the storage, expression and release of genetic variation with broad implications for adaptation and evolution.

animal behavior and cognition↗

bioRxiv2025

Spatially Resolved Microglial Expression Around Aβ Plaques in Human Alzheimers Disease Tissue

Using microglia-enriched spatial transcriptomics on human Alzheimers disease tissue, we identify distinct gene expression changes across microglia located in direct contact with plaques, in periplaque regions, and in areas distant from plaques. We define a group of plaque contact-only microglial (PCOM) genes whose expression increases exclusively in microglia directly contacting plaques. These genes show significant overlap with previously reported gene sets, suggesting that many of the well-characterised disease-associated microglia (DAM) and other AD-related gene-expression signatures are only upregulated when microglia contact plaques. We further identify distinct co-expression networks associated with disease-relevant covariates, including an immune module linked to APOE genotype and a synaptic-mitochondrial module negatively associated with Braak stage. Finally, we compare the human dataset to our previously published data from 18-month-old AppNL-F mice, generated using the same experimental paradigm and demonstrate cross-species concordance in gene expression particularly within plaque-contacting microglia.

neuroscience↗

bioRxiv2025

Transcriptomic analysis of repeat expansion-ataxias uncovers distinct non-neuronal cell type-specific signatures of disease across the human brain

Hereditary ataxias are a heterogeneous group of neurogenetic conditions characterised by the clinical syndrome of progressive loss of coordination from neurodegeneration of the cerebellum. A commonality across the most prevalent ataxias is the underlying disease mechanism secondary to expansions of short tandem DNA repeats. There is currently an incomplete understanding of the pathogenic mechanisms of these repeat expansion disorders, a core feature of which revolves around RNA-dysregulation. In this study, we used both bulk and single nuclear RNA-sequencing to study post-mortem brain tissue of human donors with a range of repeat-expansion ataxias to reveal further mechanistic insights. We compared post-mortem paired cerebellar and frontal cortex tissue bulk RNA-sequencing data from 23 ataxia patients and 22 sex-, age-matched controls from two brain banks (spinocerebellar ataxia (SCA)1, SCA2, SCA6, SCA7, SCA17, Friedreichs ataxia (FRDA), and 7 cases with unknown molecular diagnoses). We analysed bulk RNA-sequencing data for transcript usage, differential and cell-type-specific expression to transcriptomically profile these diseases. We also generated single nuclear RNA-sequencing data of the cerebellum from donors with SCA1, SCA2, SCA6 and FRDA to decipher changes in cell type proportions in the disease state. Using this approach, we found that: (i) despite the commonalities in the genetics of ataxia, there were components of their transcriptional signatures which were distinct; (ii) there were extensive transcriptional changes evident not only in the cerebellum but also the frontal cortex in ataxia cases; (iii) activation of immune and inflammatory pathways, as well as involvement of non-neuronal cell types was a feature of all ataxias to a lesser or greater extent. This study provides a novel resource to understand the mechanisms of disease in ataxia. Furthermore, taken together, these results highlight immune pathways and the role of non-neuronal cell types as early and potentially important therapeutic targets. These findings provide a map of transcriptomic changes in ataxia to further understanding of the underlying pathogenesis.

neuroscience↗