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Nilsson, I.

Publications and source records attributed to Nilsson, I..

7 recordsLinked to original sources

Aberrant microglial responses shape hypothalamic circuits in anorexia nervosa

Multimodal data indicates that microglia contribute to the pathophysiology of anorexia nervosa (AN). Here, we investigated microglial modulation of hypothalamic circuits, key regulators of energy balance, hypothesising an implication in the prolonged starvation and low body weight of AN. First, we generated microglia as well as hypothalamic and cortical neurons from patient-derived induced pluripotent stem cells (iPSCs) to discover upregulation of synapse-related genes in hypothalamic neurons, reduced microglial uptake of hypothalamic synaptic structures, and a microglial unresponsivness to the satiety hormone glucagon-like peptide-1. In an AN animal model (anx/anx mouse), spatial transcriptomics indicated hypothalamic microglial activation and disrupted microglia-synapse signaling. Despite an increased microglia density in both the arcuate nucleus (ARC) and the dorsomedial hypothalamus region (DMH), microglia displayed a decreased per cell uptake of synaptic material in Arc. Together, these data suggest that microglial responses shape hypothalamic circuits with possible implications for the maintained negative energy balance of AN.

neuroscience↗

Thrombolysis exacerbates cerebrovascular injury after ischemic stroke via a VEGF-B dependent effect on adipose lipolysis

Cerebrovascular injuries leading to edema and hemorrhage after ischemic stroke are common. The mechanisms underlying these events and how they are connected to known risk factors for poor outcome, like obesity and diabetes, is relatively unknown. Herein we demonstrate that increased adipose tissue lipolysis is a dominating risk factor for the development of a compromised cerebrovasculature in ischemic stroke. Reducing adipose lipolysis by VEGF-B antagonism improved vascular integrity by reducing ectopic cerebrovascular lipid deposition. Thrombolytic therapy in ischemic stroke using tissue plasminogen activator (tPA) leads to increased risk of hemorrhagic complications, substantially limiting the use of thrombolytic therapy. We provide evidence that thrombolysis with tPA promotes adipose tissue lipolysis, leading to a rise in plasma fatty acids and lipid accumulation in the ischemic cerebrovasculature after stroke. VEGF-B blockade improved the efficacy and safety of thrombolysis suggesting the potential use of anti-VEGF-B therapy to extend the therapeutic window for stroke management.

neuroscience↗

Reduced myofibroblast transdifferentiation and fibrotic scarring in ischemic stroke after imatinib treatment

The tyrosine kinase inhibitor imatinib has been reported to improve outcome in patients following ischemic stroke but the exact mechanism remains elusive. Here, utilizing a photothrombotic murine model of middle cerebral artery occlusion (MCAO), we show that imatinib-mediated inhibition of stroke-induced blood-brain barrier (BBB) dysfunction coincided with decreased expression of genes associated with inflammation and fibrosis in the cerebrovasculature. We found that imatinib effectively dampened stroke-induced reactive gliosis and myofibroblast transdifferentiation, whilst having very limited effect on the rest of the glia scar and on peripheral leukocyte infiltration. Further, our data suggest that consolidation of the PDGFR+ portion of the fibrotic scar in imatinib-treated mice contributes to the improvement in functional outcome compared to the vehicle controls, where the PDGFR+ scar is expanding. Comparison with human stroke transcriptome databases revealed significant overlap with imatinib-regulated genes, suggesting imatinib may modulate reactive gliosis and fibrotic scarring also in human stroke.

neuroscience↗

Spc1 regulates substrate selection for signal peptidase

Signal peptidase (SPase) cleaves the signal sequences (SSs) of secretory precursors. It contains an evolutionarily conserved membrane protein subunit, Spc1 that is dispensable for the catalytic activity of SPase, and its role remains elusive. In the present study, we investigated the function of yeast Spc1. First, we set up an in vivo SPase cleavage assay using secretory protein CPY variants with SSs modified in the n and h regions. When comparing the SS cleavage efficiencies of these variants in cells with or without Spc1, we found that signal-anchored sequences become more susceptible to cleavage by SPase without Spc1. Further, SPase-mediated processing of transmembrane (TM) segments in model membrane proteins was reduced upon overexpression of Spc1. Spc1 was co-immunoprecipitated with membrane proteins carrying uncleaved signal-anchored or TM segments. These results suggest a role of Spc1 in shielding TM segments from SPase action, thereby contributing to accurate substrate selection for SPase.

biochemistry↗

Circumpolar diversification of the Ixodes uriae tick virome

Ticks (order: Ixodida) are a highly diverse and ecologically important group of ectoparasitic blood-feeding organisms. One such species, the seabird tick (Ixodes uriae), is widely distributed around the circumpolar regions of the northern and southern hemispheres. It has been suggested that Ix. uriae spread from the southern to the northern circumpolar region millions of years ago and has remained isolated in these regions ever since. Such a profound biographic subdivision provides a unique opportunity to determine whether viruses associated with ticks exhibit the same evolutionary patterns as their hosts. To test this, we collected Ix. uriae specimens near a Gentoo penguin (Pygoscelis papua) colony at Neko harbour, Antarctica, and from migratory birds - the Razorbill (Alca torda) and the Common murre (Uria aalge) - on Bonden island, northern Sweden. Through meta-transcriptomic next- generation sequencing we identified 16 RNA viruses, seven of which were novel. Notably, we detected the same species, Ronne virus, and two closely related species, Bonden virus and Piguzov virus, in both hemispheres indicating that there have been at least two cross- circumpolar dispersal events. Similarly, we identified viruses discovered previously in other locations several decades ago, including Gadgets Gully virus, Taggert virus and Okhotskiy virus. By identifying the same or closely related viruses in geographically disjunct sampling locations we therefore provide evidence for virus dispersal within and between the circumpolar regions. In marked contrast, our phylogenetic analysis revealed no movement of the Ix. uriae hosts between the same locations. Combined, these data suggest that migratory birds are responsible for the movement of viruses at both the local and global scales. Author summary/ImportanceAs host populations diverge, so may those microorganisms, including viruses, that are dependent on those hosts. To examine this key issue in host-microbial evolution we compared the co-phylogenies of the seabird tick, Ixodes uriae, and their RNA viruses sampled from the far northern and southern hemispheres. Despite the huge geographic distance between them, phylogeographic analysis reveals that the same viruses were found both within and between the northern and southern circumpolar regions, most likely reflecting transfer by virus-infected migratory birds. In contrast, genomic data suggested that the Ix. uriae populations were phylogenetically distinct between the northern and southern hemispheres. This work emphasises the importance of migratory birds and ticks as vectors and sources of virus dispersal and introduction at both the local and global scales.

microbiology↗

Membrane integration and topology of RIFIN and STEVOR proteins of the Plasmodium falciparum parasite

The malarial parasite Plasmodium, infects red blood cells by remodeling them and transporting its own proteins to their cell surface. These proteins trigger adhesion of infected cells to uninfected cells (rosetting), and to the vascular endothelium, obstructing blood flow and contributing to pathogenesis. RIFINs (P. falciparum-encoded repetitive interspersed families of polypeptides) and STEVORs (subtelomeric variable open reading frame), are two classes of proteins that are involved in rosetting. Here we study the membrane insertion and topology of three RIFIN and two STEVOR proteins, employing a well-established assay that uses N-linked glycosylation of sites within the protein as a measure to assess the topology a protein adopts when inserted into the ER membrane. Our results indicate that all the proteins tested assume an overall topology of Ncyt-Ccyt, with predicted transmembrane helices TM1 and TM3 integrated into the ER membrane. We also show that the segments predicted as TM2 do not reside in the membrane. Our conclusions are consistent with other recent topology studies on RIFIN and STEVOR proteins.

biochemistry↗

Astrotactins 1 and 2 have similar membrane topology and mature via endoproteolytic cleavage catalyzed by signal peptidase

Astrotactins 1 and 2 (Astn1, Astn2) are membrane proteins that function in glial-guided migration, receptor trafficking and synaptic plasticity in brain, as well as in planar polarity pathways in skin. Here, we have mapped the topologies of mouse Astn1 and Astn2 in rough microsomal membranes (RMs) using glycosylation mapping and protease-protection assays, and find that Astn2 has a cleaved N-terminal signal peptide (SP), an N-terminal domain located in the lumen of the RMs (topologically equivalent to the extracellular surface in cells), two transmembrane helices (TMHs), and a large C-terminal lumenal domain. We find that Astn1 has the same topology as Astn2 but see no evidence of SP cleavage. Both Astn1 and Astn2 mature through endoproteolytic cleavage in the second TMH; importantly, we identify the endoprotease responsible for the maturation of Astn1 and Astn2 as signal peptidase. Differences in the degree of the maturation of Astn1 and Astn2 possibly contribute to the higher levels of the C-terminal domain of Astn1 detected on the CNS neuronal membranes and to the different functions of Astn1 and Astn2.

neuroscience↗