Biology subjects

Schirmeier, S.

Publications and source records attributed to Schirmeier, S..

7 recordsLinked to original sources

bioRxiv2026

Restoration of (nor)adrenergic-like Ca2+ signalling counteracts age-related motor decline

Aging disrupts neural function, but whether impaired noradrenergic control of brain metabolism contributes to functional decline remains unclear. Using genetically encoded fluorescent sensors we measured metabolic and signaling responses in neurons and glia of living Drosophila brains following stimulation with octopamine, the invertebrate analogue of noradrenaline. Aging was accompanied by neurodegeneration, reduced locomotion and enhanced oxidative whole-brain metabolism. Octopamine increased D-glucose uptake selectively in astrocytes and elevated L-lactate in both astrocytes and neurons, consistent with astrocytic glycolysis coupled to neuronal L-lactate uptake; monocarboxylate transporter inhibition caused selective astrocytic L-lactate accumulation. In aged animals octopamine-evoked metabolic responses in astrocytes and neural Ca2+ transients were markedly reduced. This impairment was associated with lower expression of adrenoceptor-like tyramine 1 receptor (Tyr1R). Selective Tyr1R overexpression in (nor)adrenergic-like Tdc2 neurons prolonged lifespan, restored Ca2+ signalling and improved locomotor performance. These findings identify Tyr1R-dependent Ca2+ signalling as an age-sensitive regulator of brain metabolism and motor function.

neuroscience↗

bioRxiv2024

An essential role for glial cells in postingestive nutrient sensing

Behavioral flexibility is an essential trait for survival of any organism. For example, choosing an appropriate food source is vital. To do so, the foods nutritive value needs to be evaluated. Several studies have demonstrated that Drosophila melanogaster larvae and adults, as mammals, are able to distinguish between nutritious and non-nutritious carbohydrates independent of their taste. Several groups of neurons have been implicated in postprandial sugar sensing in adult flies (Dus et al., 2011, 2015; Miyamoto et al., 2012; Park et al., 2016; Musso et al., 2023). In larvae, neurons expressing Gr43a, a fructose receptor, have been shown to be implicated in postingestive glucose sensing (Mishra et al., 2013). How can a fructose sensor mediate glucose sensing? We show that postingestive glucose, and also sorbitol, sensing involves carbohydrate conversion into fructose via the polyol pathway in glial cells. Glia-derived fructose is subsequently sensed via Gr43a expressed in neurons, which leads to behavioral adaptation. Thus, in postingestive nutrient sensing, the glial cells play a central role in information processing and regulation of behavior.

neuroscience↗

bioRxiv2021

A prior exposure to Serratia marcescens or xenobiotics primes Drosophila enterocytes against a recurring cytoplasmic purge

The cytoplasmic extrusion of enterocytes is a fast response to an exposure to pore-forming toxin (PFT)-producing bacteria whereby their apical cytoplasm is extruded into the intestinal lumen. As a result of this purge, the intestinal epithelium becomes thin prior to a subsequent recovery. We report here that the ingestion of ethanol or caffeine induces a similar response, which suggests that a common purging process is triggered by bacterial toxins and abiotic toxicants. We also delineate an additional mechanism that is initiated by these stimuli that we refer to as priming. The initial exposure of the intestinal epithelium to either PFT or xenobiotics protects enterocytes against a further round of purging upon a second bacterial infection. Priming prevents the epithelium from being persistently thin in the context of chronic intestinal infections. We have identified the upper part of the p38b MAPK pathway as well as the homeobox-containing transcription factors E5/EMS as being required for priming and not for the regrowth of enterocytes after the cytoplasmic purge. Unexpectedly, the priming process appears to function cell-nonautonomously. Our findings suggest that the cytoplasmic purge extrusion has been selected because it constitutes a fast reaction to accidental exposure to bacterial toxins or toxicants.

physiology↗

bioRxiv2020

Highly responsive single-fluorophoreindicator to explore lactate dynamics in high calcium environments

Lactate is an energy substrate and intercellular signaling molecule with multiple bodily functions. Lactate has physiological roles in neurogenesis, axon integrity, memory consolidation, immune response, exercise, adipose tissue lipolysis, etc, and is involved in inflammation, cancer and neurodegeneration. The FRET lactate indicator Laconic has been instrumental in the discovery of mechanisms involved in neurometabolic coupling, and has advanced the understanding of lactate transport, glycolysis and mitochondrial physiology. However, the low fluorescent response and the complex saturation kinetics of Laconic limit its use for high-throughput screening and quantitation. Using the bacterial periplasmic binding protein TTHA0766 from Thermus thermophilus, we have now developed the first single-fluorophore indicator for lactate. The sensor exhibited an intensiometric fluorescence increase of {Delta}F/F0 3.0 and a single binding site with a KD of 293 M. The fluorescence is not affected by other monocarboxylates or pH. However, it is sensitive to Ca2+ in the nanomolar range. Targeting of the sensor to the endoplasmic reticulum revealed that this organelle presents a high permeability for lactate. The functionality of the sensor in living tissue is demonstrated in the brain of Drosophila melanogaster larvae. This indicator, which we have termed CanlonicSF, is well suited to explore lactate dynamics in environments with micromolar Ca2+ or higher, such as the endoplasmic reticulum and the extracellular space.

cell biology↗

bioRxiv2020

Starvation-induced regulation of carbohydrate transport at the blood-brain barrier is TGF-β-signaling dependent

During hunger or malnutrition animals prioritize alimentation of the brain over other organs to ensure its function and thus their survival. This so-called brain sparing is described from Drosophila to humans. However, little is known about the molecular mechanisms adapting carbohydrate transport. Here, we used Drosophila genetics to unravel the mechanisms operating at the blood-brain barrier (BBB) under nutrient restriction. During starvation, expression of the carbohydrate transporter Tret1-1 is increased to provide more efficient carbohydrate uptake. Two mechanisms are responsible for this increase. Similarly to the regulation of mammalian GLUT4, Rab-dependent intracellular shuttling is needed for Tret1-1 integration into the plasma membrane, even though Tret1-1 regulation is independent of insulin signaling. In addition, starvation induces transcriptional upregulation controlled by TGF-{beta} signaling. Considering TGF-{beta}-dependent regulation of the glucose transporter GLUT1 in murine chondrocytes, our study reveals an evolutionarily conserved regulatory paradigm adapting the expression of sugar transporters at the BBB.

cell biology↗

bioRxiv2019

A highly responsive pyruvate sensor reveals pathway-regulatory role of the mitochondrial pyruvate carrier MPC

Mitochondria generate ATP and building blocks for cell growth and regeneration, using pyruvate as the main substrate. Here we introduce PyronicSF, a user-friendly GFP-based sensor of improved dynamic range that enables real-time subcellular quantitation of mitochondrial pyruvate transport, concentration and flux. We report that cultured mouse astrocytes maintain mitochondrial pyruvate in the low micromolar range, below cytosolic pyruvate, which means that the mitochondrial pyruvate carrier MPC controls the decision between respiration and anaplerosis/gluconeogenesis in an ultrasensitive fashion. The functionality of the sensor in living tissue is demonstrated in the brain of Drosophila melanogaster larvae. Mitochondrial subpopulations are known to coexist within a given cell, which differ in their morphology, mobility, membrane potential, and vicinity to other organelles. The present tool can be used to investigate how mitochondrial diversity relates to metabolism, to study the role of MPC in disease, and to screen for small-molecule MPC modulators.

cell biology↗

bioRxiv2017

RhlR, but not RhlI, allows P. aeruginosa bacteria to evade Drosophila Tep4- mediated opsonization

When Drosophila flies feed on Pseudomonas aeruginosa strain PA14, some bacteria cross the intestinal barrier and start proliferating inside the hemocoel. This process is limited by hemocytes through phagocytosis. We have previously shown that the PA14 quorum-sensing regulator RhlR is required for these bacteria to elude the cellular immune response. RhlI synthesizes the auto-inducer signal that activates RhlR. Here, we compare the null mutant phenotypes of rhlR and rhlI in a variety of infection assays in Drosophila and in the nematode Caenorhabditis elegans. Surprisingly, in Drosophila, unlike{Delta} rhlR mutants,{Delta} rhlI mutants are only modestly attenuated for virulence and are poorly phagocytosed and opsonized in a Thioester-containing Protein4-dependent manner. Likewise, {Delta}rhlI but not {Delta}rhlR mutants colonize the digestive tract of C. elegans and kill it as efficiently as wild-type PA14. Thus, RhlR has an RhlI-independent function in eluding detection or counter-acting the action of the immune system. In contrast to the intestinal infection model, Tep4 mutant flies are more resistant to PA14 in a septic injury model, which also depends on rhlR. Thus, the Tep4 putative opsonin can either be protective or detrimental to host defense depending on the infection route.

immunology↗