Biology subjects

Curran, O. E.

Publications and source records attributed to Curran, O. E..

3 recordsLinked to original sources

bioRxiv2025

Spatial dynamics of IFITM1: a core component of the interferon-stimulated gene-resistance signature in glioma

The IFITM1 protein is a key component of the Interferon-Stimulated Gene (ISG) network, which has been linked to treatment-resistant signatures in various cancers, including glioblastoma (GBM). Despite its impact, the mechanisms underlying IFITM1s role in cancer remain poorly understood. Here, we demonstrate that the spatial dynamics of IFITM1 localisation are highly context-dependent, particularly in GBM tissue. In the vasculature, IFITM1 is predominantly localised to the plasma membrane of endothelial cells. However, when present in a subset of cancer stem cells, IFITM1 adopts a distinct perinuclear location, where it co-localises with IFITM3 and is notably absent from the membrane. The spatial dynamics of IFITM1 localisation was investigated in patient-derived glioma stem cells (GSCs), primary endothelial cells and engineered cell lines. Endogenous IFITM1 localised primarily to assemblies in the perinuclear space, however loss of functional IFITM3 led to a shift in the distribution of the protein to a predominantly membrane location. In contrast, IFITM3 localisation was unaffected by the loss of IFITM1. The results were recapitulated by transient expression of IFITM1 or -3 into double knockout (DKO) GSCs and by using an engineered system where IFITM1 expression was IFN-independent. Co-expression studies demonstrate that IFITM3 is sufficient to localise IFITM1 to vesicle structures in the perinuclear space and that mutant forms of IFITM3 lead to retention of IFITM1 primarily at the plasma membrane. Our data highlights dynamic changes in the subcellular localisation of IFITM1 suggesting that distinct functions of this resistance factor may present a specific target for therapeutic intervention.

cancer biology↗

bioRxiv2020

Species differences in the cerebellar distribution of six members of the Kv1 channel subfamily.

Comprehensive studies on the distribution of the Kv1 subfamily have been performed in rat (Chung et al., 2001) and gerbil (Chung et al., 2005), but not in mouse or human. We hypothesized that species differences may exist in the localization of these proteins. Two sets of polyclonal antibodies to Kv1.1-6 were used. Immunohistochemistry was performed on archived, formalin-fixed tissue from disease-free human, monkey and mouse cerebellum. Mouse staining corresponded to that described in rat and gerbil, with strong Kv1.1 and Kv1.2 immunoreactivities in the basket cell pinceau at the base of Purkinje cells. Kv1.3, Kv1.4, Kv1.5 and Kv1.6 were predominantly expressed in Purkinje cells. Human and monkey samples showed a similar pattern to mouse for Kv1.1, Kv1.2, Kv1.3 and Kv1.5. However, little or no Purkinje cell staining was seen in the primates with Kv1.4 and Kv1.6, and strong stellate cell expression was noted. All staining was abolished by cognate peptide blocking. Similar distributions were seen with both sets of antibodies. We conclude that there are marked species differences in the distribution of Kv1.4 and Kv1.6 between primates and rodents. Choosing appropriate animal models for studying physiological and disease processes may prove vital for translating research outcomes into clinical applications.

neuroscience↗

bioRxiv2020

The human and mouse synaptome architecture of excitatory synapses show conserved features.

Large-scale mapping of the location of synapses and their molecular properties in the mouse has shown that diverse synapse types are spatially distributed across the brain. The diversity of synapses is known as the synaptome and the spatial distribution as the synaptome architecture. Synaptome maps in the mouse show each brain region has a characteristic compositional signature. The signature can store behavioral representations and is modified in mouse genetic models of human disease. The human synaptome remains unexplored and whether it has any conserved features with the mouse synaptome is unknown. As a first step toward creating a human synaptome atlas, we have labelled and imaged synapses expressing the excitatory synapse protein PSD95 in twenty human brain regions in four phenotypically normal individuals. We quantified the number, size and intensity of approximately a billion individual synaptic puncta and compared their regional distributions. We found that each region showed a distinct signature of synaptic puncta parameters. Comparison of brain regions showed the synaptome of cortical and hippocampal structures were similar but distinct to the synaptome of cerebellum and brainstem. Comparison of human and mouse synaptome revealed conservation of synaptic puncta parameters, hierarchical organization of brain regions and network architecture. These data show that the synaptome of humans and mouse share conserved features despite the 1000-fold difference in brain size and 90 million years since a common ancestor. This first draft human synaptome atlas illustrates the feasibility of generating a systematic atlas of the human synaptome in health and disease.

neuroscience↗