Biology subjects

Benz, J.

Publications and source records attributed to Benz, J..

5 recordsLinked to original sources

bioRxiv2026

Mitochondrial turnover at central GABAergic synapses governs vulnerability to epileptic seizures

Mitochondrial dysfunction has long been known to underlie neurodegeneration, yet the contribution of mitochondrial turnover dynamics to functional aspects of defined synaptic circuits remains poorly understood. Here, we show that the mitochondrial proteome and turnover rates of hippocampal glutamatergic and GABAergic neurons is differentially remodelled by experience, with distal axon terminals of somatostatin-positive neurons exhibiting most dramatic changes, suggesting a form of metabolic plasticity at GABAergic synapses coupled to circuit activity. Conditional ablation of the mitochondrial transport proteins MIRO1 or TRAK1 (whose human mutations cause congenital epilepsy) stalled turnover at axon terminals driving loss of cristae, without affecting synapse or neuron integrity. The resulting reduction in synaptic GABA levels destabilized network oscillations and led to hyperexcitability, culminating in recurrent seizures and premature death. Post-weaning gene therapy efficiently reversed mitochondrial alterations and ameliorated the epileptic phenotype, underscoring the crucial role of mitochondrial turnover at central GABAergic synapses for balancing network excitability.

neuroscience↗

bioRxiv2025

SARM1 base-exchange inhibitors induce SARM1 activation and neurodegeneration at low doses

SARM1 has emerged as a promising therapeutic target in neurology due to its central role in axonal degeneration and its amenability to different modes of small molecule inhibition. One chemical approach to modulate SARM1 involves orthosteric inhibition via a SARM1-mediated base-exchange reaction between a small molecule and nicotinamide adenine dinucleotide (NAD+), the substrate of SARM1, to generate the active inhibitor. Here, we report that subinhibitory concentrations of SARM1 base-exchange inhibitors (BEIs) paradoxically increase SARM1 activity and worsen SARM1-induced cell death and neuronal damage in vitro. Low dose administration of RO-7529, a SARM1 BEI, exacerbated experimental autoimmune encephalomyelitis (EAE)-induced neurodegeneration in vivo. Our data highlight a unique pharmacological feature of SARM1 BEIs that may limit their therapeutic application in disorders associated with SARM1 activation and axonal degeneration.

neuroscience↗

bioRxiv2025

Glycolytic flux sustains human Th1 identity and effector function via STAT1 glycosylation

Fate decisions of T helper (Th) cells are tightly linked to their metabolic states, but precise mechanistic links remain unknown, especially in humans. Using in vitro stimulation in combination with gene editing we studied how metabolic regulation shapes human Th1 cell identity and effector function. Differentiated Th1 cells displayed elevated STAT1 phosphorylation at Tyr701 and Ser727 as well as heightened T-bet and IFN{gamma} expression, which were dampened by CRISPR/Cas9-mediated STAT1 deletion. Metabolic profiling revealed enhanced glycolytic activity in Th1 in comparison to Act.T cells, evidenced by increased extracellular acidification rate, ATP production via glycolysis, glucose uptake, lactate secretion and NADH abundance. SCENITH analysis demonstrated elevated glycolysis-dependent anabolic activity of Th1 cells. Inhibition of glycolysis reduced IFN{gamma} production and STAT1 phosphorylation independent of JAK1/2 activity, STAT1 abundance or SHP-2 activity, implicating glycolysis directly in sustaining STAT1-mediated Th1 functionality. Mechanistically, O-Glycosylation, facilitated by O-Glycosyltransferase, emerged as pivotal in modulating STAT1 activity, as evident through immunoprecipitation and Western blot analysis. Pharmaceutical O-Glycosyltransferase inhibition prevented Th1 differentiation as well as STAT1 O-glycosylation. CRISPR/Cas9 mediated mutation of the O-glycosylation sites Ser499 and Thr510 sites diminished STAT1 Ser727 phosphorylation and IFN{gamma} synthesis. Together, this study highlights glycolysis as key regulator of human Th1 cell identity and effector function, with STAT1 O-Glycosylation selectively maintaining Th1 effector capacity. This mechanism could be explored to safeguard Th1 cells in antiviral immunity and autoimmunity. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/636644v1_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@1ee58aeorg.highwire.dtl.DTLVardef@1001af6org.highwire.dtl.DTLVardef@1ea2ed7org.highwire.dtl.DTLVardef@1a943fc_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2022

Grazers and predators mediate the post-settlement bottleneck in Caribbean octocoral forests

Caribbean octocorals have not suffered the decades long decline in abundance that has plagued reef-building scleractinian corals. Their success and the formation of octocoral forests has been attributed to their continuing recruitment to reef habitats. Assessing the processes controlling recruitment is essential to understanding the success of octocorals and predicting their future. Benthic grazers on coral reefs can facilitate the growth and recruitment of corals by reducing the abundance of competitive algal turfs and macroalgae or hinder corals through predation of coral tissue and recruits. We assessed the effects of grazing by fishes and the sea urchin Diadema antillarum and mesofaunal predation on octocoral recruitment in a series of manipulative experiments using varying grazer/predator exclusion and inclusion conditions in in situ and ex situ experiments. Exposure to fish and urchin grazing significantly reduced survival and recruitment of single-polyp octocorals, while turf-associated mesofauna did not significantly affect neither recruitment nor survival. We also found a positive relationship between octocoral recruitment and turf algae, a potential related response to the deleterious effect of grazing exposure. These data suggest that grazers and predators mediate the mortality bottleneck characteristic of recruitment. Thus, the declines in the abundance of grazing fishes and urchins throughout the Caribbean may have contributed to the increase in abundance of octocorals in the Caribbean, concurrent with the loss of scleractinians.

ecology↗

bioRxiv2022

A potent and selective inhibitor for the modulation of MAGL activity in the neurovasculature

Chronic inflammation and blood-brain barrier dysfunction are key pathological hallmarks of neurological disorders such as multiple sclerosis, Alzheimers disease and Parkinsons disease. Major drivers of these pathologies include pro-inflammatory stimuli such as prostaglandins, which are produced in the central nervous system by the oxidation of arachidonic acid in a reaction catalyzed by the cyclooxygenases COX1 and COX2. Monoacylglycerol lipase hydrolyzes the endocannabinoid signaling lipid 2-arachidonyl glycerol, enhancing local pools of arachidonic acid in the brain and leading to cyclooxygenase-mediated prostaglandin production and neuroinflammation. Monoacylglycerol lipase inhibitors were recently shown to act as effective anti-inflammatory modulators, increasing 2-arachidonyl glycerol levels while reducing levels of arachidonic acid and prostaglandins, including PGE2 and PGD2. In this study, we characterized a novel, highly selective, potent and reversible monoacylglycerol lipase inhibitor (MAGLi 432) in a mouse model of lipopolysaccharide-induced blood-brain barrier permeability and in both human and mouse cells of the neurovascular unit: brain microvascular endothelial cells, pericytes and astrocytes. We confirmed the expression of monoacylglycerol lipase in specific neurovascular unit cells in vitro, with pericytes showing the highest expression level and activity. However, MAGLi 432 did not ameliorate lipopolysaccharide-induced blood-brain barrier permeability in vivo or reduce the production of pro-inflammatory cytokines in the brain. Our data confirm monoacylglycerol lipase expression in mouse and human cells of the neurovascular unit and provide the basis for further cell-specific analysis of MAGLi 432 in the context of blood-brain barrier dysfunction caused by inflammatory insults.

neuroscience↗