Biology subjects

Radulescu, C. I.

Publications and source records attributed to Radulescu, C. I..

4 recordsLinked to original sources

bioRxiv2026

Glial subcellular specialisation resolved with high resolution spatial transcriptomics

Cells in the brain have complex structures with extended processes. This complex morphology supports diverse specialized functions in health and disease, and specifically, cell processes appear to be critical for cellular integration and signalling. Here, we developed a new spatial averaging framework to recover and interrogate molecular phenotypes of glial processes in spatial transcriptomics (ST) data. We characterised cell type specific signatures associated with processes of astrocytes and microglia in both mouse and human brain tissue. Astrocytic processes were enriched for transcripts related to neuronal support relative to their soma, while microglial processes preferentially expressed genes linked to specific microglial states. When investigated in tissue from brains with Alzheimers Disease (AD) pathology, we found that local amyloid-{beta} pathology was associated with subcellular differences in transcriptomes in both an amyloid-{beta} mouse model and human AD patient tissue. Specifically, astrocytic and microglial processes oriented toward amyloid-{beta} plaques exhibited distinct molecular changes in comparison to processes extending away into plaque free areas, suggesting polarized glial responses to pathology. Our work thus outlines a general method for the selective characterisation of transcriptomics of glial processes in mouse and human ST data and provides evidence for differential transcriptomic responses between the soma and processes of glia in health and disease. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=139 SRC="FIGDIR/small/737168v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@157455corg.highwire.dtl.DTLVardef@8ac0a2org.highwire.dtl.DTLVardef@16ccbf5org.highwire.dtl.DTLVardef@1c24cd0_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2022

Translocator protein is a marker of activated microglia in rodent models but not human neurodegenerative diseases

Microglial activation plays central roles in neuro-inflammatory and neurodegenerative diseases. Positron emission tomography (PET) targeting 18kDa Translocator Protein (TSPO) is widely used for localising inflammation in vivo, but its quantitative interpretation remains uncertain. We show that TSPO expression increases in activated microglia in mouse brain disease models but does not change in a non-human primate disease model or in common neurodegenerative and neuroinflammatory human diseases. We describe genetic divergence in the TSPO gene promoter, consistent with the hypothesis that the increase in TSPO expression in activated myeloid cells is unique to a subset of species within the Muroidea superfamily of rodents. We show that TSPO is mechanistically linked to classical pro-inflammatory myeloid cell function in rodents but not humans. These data emphasise that TSPO expression in human myeloid cells is related to different phenomena than in mice, and that TSPO PET reflects density of inflammatory cells rather than activation state.

neuroscience↗

bioRxiv2019

Integrative analysis identifies key molecular signatures underlying neurodevelopmental deficits in Fragile X Syndrome

Fragile X syndrome (FXS) is an incurable neurodevelopmental disorder with no effective treatment. FXS is caused by epigenetic silencing of FMR1 and loss of FMRP expression. To investigate the consequences of FMRP deficiency in the context of human physiology, we established isogenic FMR1 knockout (FMR1KO) human embryonic stem cells (hESCs). Integrative analysis of the transcriptomic and proteomic profiles of hESC-derived FMRP-deficient neurons revealed several dysregulated pathways important for brain development including processes related to axon development, neurotransmission, and the cell cycle. We functionally validated alterations in a number of these pathways, showing abnormal neural rosette formation and increased neural progenitor cell proliferation in FMR1KO cells. We further demonstrated neurite outgrowth and branching deficits along with impaired electrophysiological network activity in FMRP-deficient neurons. Using isogenic FMR1KO hESC-derived neurons, we reveal key molecular signatures and neurodevelopmental abnormalities arising from loss of FMRP. We anticipate that the FMR1KO hESCs and the neuronal transcriptome and proteome datasets will provide a platform to delineate the pathophysiology of FXS in human neural cells.

neuroscience↗

bioRxiv2018

Manipulation of microbiota reveals altered myelination and white matter plasticity in a model of Huntington disease

Structural and molecular myelination deficits represent early pathological features of Huntington disease (HD). Recent evidence from germ-free (GF) animals suggests a role for microbiota-gut-brain bidirectional communication in the regulation of myelination. In this study, we aimed to investigate the impact of microbiota on myelin plasticity and oligodendroglial population dynamics in the mixed-sex BACHD mouse model of HD. Ultrastructural analysis of myelin in the corpus callosum revealed alterations of myelin thickness in BACHD GF compared to specific-pathogen free (SPF) mice, whereas no differences were observed between wild-type (WT) groups. In contrast, myelin compaction was altered in all groups when compared to WT SPF animals. Levels of myelin-related proteins were generally reduced, and the number of mature oligodendrocytes was decreased in the prefrontal cortex under GF compared to SPF conditions, regardless of genotype. Minor differences in commensal bacteria at the family and genera levels were found in the gut microbiota of BACHD and WT animals housed in standard living conditions. Our findings indicate complex effects of a germ-free status on myelin-related characteristics, and highlight the adaptive properties of myelination as a result of environmental manipulation.

neuroscience↗