Biology subjects

Engel, S.

Publications and source records attributed to Engel, S..

4 recordsLinked to original sources

bioRxiv2024

Choroid plexus enlargement in acute neuroinflammation is tightly interrelated to the tyrosine receptor signalling

The choroid plexus (ChP) plays a crucial function in neuroinflammation of the central nervous system and in the immune response of the brain during neurodegeneration. Recent studies described a massive ChP enlargement in patients with multiple sclerosis (MS) and active disease courses, but also in several other neuroinflammatory and neurodegenerative conditions. Nevertheless, the exact basis and pathophysiology behind ChP hypertrophy remains unclear. This study was designed to evaluate the association of cerebrospinal fluid (CSF) proteomic spectra with brain MRI-derived volumetric measures of ChP in two independent cohorts of MS patients, and to translationally validate the related molecular mechanisms in the transcriptomic analysis of the ChP properties in a mouse model of experimental autoimmune encephalomyelitis (EAE). Our analysis revealed five enriched proteins (NTRK2, ADAM23, SCARB2, CPM, CNTN5) significantly associated with the ChP volumes in both of the MS cohorts. These proteins relate closely to mechanisms of cellular communication, function (e.g. transmembrane tyrosine receptor signalling (RTK) and vascular endothelial growth) and pathways involved in the regulation of cellular plasticity (e.g. neuron differentiation, axonal remodelling and myelin regulation) as depicted by molecular function analysis and validation of the results in the transcriptome from ChP tissue specific for EAE. This work provides conclusive new evidence for the role of ChP in the context of neuroinflammation and neurodegeneration, demonstrating the intriguing relationships between ChP enlargement, CSF dynamics, and the development of neuroinflammatory and neurodegenerative diseases. Our results are encouraging for the development of new therapeutic avenues (i.e. targeting RTK signalling). One sentence summaryTyrosine receptor signalling is tightly associated with choroid plexus enlargement and is key in CSF dynamics during a neuroinflammatory attack in MS

neuroscience↗

bioRxiv2023

Subregion and sex differences in ethanol activation of cholinergic and glutamatergic cells in the mesopontine tegmentum

Ethanol engages cholinergic signaling and elicits endogenous acetylcholine release. Acetylcholine input to the midbrain originates from the mesopontine tegmentum (MPT), which is composed of the laterodorsal tegmentum (LDT) and the pedunculopontine tegmental nucleus (PPN). We investigated the effect of acute and chronic ethanol administration on cholinergic and glutamatergic neuron activation in the PPN and LDT in male and female mice. We show that ethanol selectively activates neurons of the PPN and not the LDT in male mice. Acute 4.0 g/kg and chronic 15 daily injections of 2.0 g/kg i.p. ethanol induced Fos expression in cholinergic and glutamatergic PPN neurons in male mice, whereas cholinergic and glutamatergic neurons of the LDT were unresponsive. In contrast, acute or chronic ethanol at either dose or duration had no effect on the activation of cholinergic or glutamatergic neurons in the MPT of female mice. Female mice had higher level of baseline activation in cholinergic neurons compared with males. We also found a population of co-labeled cholinergic and glutamatergic neurons in the PPN and LDT which were highly active in the saline- and ethanol-treated groups in both sexes. These findings illustrate the complex differential effects of ethanol across dose, time point, MPT subregion and sex.

pharmacology and toxicology↗

bioRxiv2023

Large-scale in-cell photocrosslinking at single residue resolution reveals the molecular basis for glucocorticoid receptor regulation by immunophilins

The large immunophilins FKBP51 and FKBP52 play key roles in the Hsp90-mediated maturation of steroid hormone receptors, which is crucial for stress-related disorders and correct sexual embryonic development, respectively 1-3. A prominent regulatory target is the glucocorticoid receptor (GR), whose activation is repressed by FKBP51 4,5 and facilitated by FKBP52 6,7. Despite their vital roles, the molecular modes of action of FKBP51 and FKBP52 are poorly understood since the transient key states of FKBP-mediated GR-regulation have remained experimentally elusive. Here we present the architecture and functional annotation of FKBP51-, FKBP52- and p23-containing Hsp90-apoGR preactivation complexes, trapped by systematic incorporation of photoreactive amino acids 8,9 inside human cells. The identified crosslinking sites depended on a functional Hsp90 chaperone cycle, were disrupted by GR activation, and clustered in characteristic patterns, defining the relative orientation and contact surfaces within the FKBP/p23-apoGR complexes. Strikingly, GR binding to the FKBPFK1 but not the FKBPFK2 domains were modulated by FKBP ligands, explaining the lack of FKBP51-mediated GR derepression by certain classes of FKBP ligands. These findings show how FKBP51 and FKBP52 differentially interact with the apoGR ligand binding domain, they explain the differentiated pharmacology of FKBP51 ligands, and provide a structural basis for the development of FKBP ligands with higher efficacy.

biochemistry↗

bioRxiv2021

PATAN-domain response regulators interact with the Type IV pilus motor to control phototactic orientation in the cyanobacterium Synechocystis sp. PCC 6803

Many prokaryotes show complex behaviors that require the intricate spatial and temporal organization of cellular protein machineries, leading to asymmetrical protein distribution and cell polarity. One such behavior is cyanobacterial phototaxis which relies on the dynamic localization of the Type IV pilus motor proteins in response to light. In the cyanobacterium Synechocystis, various signaling systems encompassing chemotaxis-related CheY- and PatA-like response regulators are critical players in switching between positive and negative phototaxis depending on the light intensity and wavelength. In this study, we show that PatA-type regulators evolved from chemosensory systems. Using fluorescence microscopy and yeast-two-hybrid analysis, we demonstrate that they localize to the inner membrane, where they interact with the N-terminal cytoplasmic domain of PilC and the pilus assembly ATPase PilB1. By separately expressing the subdomains of the response regulator PixE, we confirm that only the N-terminal PATAN domain interacts with PilB1, localizes to the membrane, and is sufficient to reverse phototactic orientation. These experiments established that the PATAN domain is the principal output domain of PatA-type regulators which we presume to modulate pilus extension by binding to the pilus motor components.

microbiology↗