Biology subjects

Ulrich, K.

Publications and source records attributed to Ulrich, K..

7 recordsLinked to original sources

bioRxiv2025

Early postnatal CA3 hyperexcitability drives hippocampal development and epileptogenesis in SCN2A developmental and epileptic encephalopathy

Developmental and epileptic encephalopathies caused by pathogenic variants in SCN2A (SCN2A-DEE), encoding the voltage-gated sodium channel Nav1.2, present with early-life seizures, developmental delay, and increased mortality. Using a novel Scn2a p.A263V gain-of-function (GOF) mouse model, we demonstrate gene-dose and background-dependent phenotypes ranging from self-limited neonatal seizures to chronic epilepsy with high mortality. In vivo electrophysiology revealed hippocampal seizures as early as postnatal day 2.5, with CA3-driven gamma oscillations preceding seizure onset. CA3 and CA1 pyramidal neurons exhibited transient hyperexcitability during early postnatal development, resolving by P24-30. Single-cell RNA sequencing uncovered gene dose-dependent accelerated maturation of hippocampal networks, peaking at P7, alongside widespread transcriptional changes in excitatory and inhibitory neurons. In adulthood, persistent hippocampal network alterations emerged, marked by reduced mid-gamma oscillations and theta-gamma coupling. Our findings establish hippocampal CA3 hyperexcitability as an early driver of epileptogenesis in SCN2A-DEE and highlight it as a potential therapeutic target to mitigate disease progression.

neuroscience↗

bioRxiv2024

A dynamic redox switch turns TRC40 into a chaperone protecting human cells against ATP-depleting, oxidative stress

Oxidative stress represents a major challenge for cellular proteostasis. The accumulation of reactive oxygen species, such as hydrogen peroxide, impairs the fidelity of protein biosynthesis and causes non-specific oxidative protein modifications and aggregation. This situation is further aggravated by the oxidative stress-mediated drop in cellular ATP levels, which reduces the activity of ATP-dependent chaperones and proteases. We now demonstrate that to cope with oxidative unfolding stress, human cells rely on the moonlighting function of TRC40, which turns from an ATP-dependent targeting factor into an ATP-independent chaperone upon oxidation. Controlled by a highly conserved redox switch, oxidized TRC40 forms chaperone-active tetramers and high-molecular complexes which prevent the aggregation of unfolding proteins. Acute oxidative stress leads to the reversible formation of distinct TRC40 foci, associated with the canonical chaperones Hsp70 and Hsp110, suggesting a role of these stress-induced structures in recovering and sorting aberrant proteins. Consistently, we discovered that TRC40 is essential upon ATP-depleting, oxidative stress conditions to counteract the accumulation of mis- and unfolded proteins, which are rapidly cleared in an TRC40-dependent manner. Our data reveal that TRC40 is an integral part of protein quality control and support its role as a triaging factor in cellular proteostasis.

cell biology↗

bioRxiv2022

STING1 activation in brain endothelium by Plasmodium-sequestered heme leads to lethal cerebral malaria through activation of type I IFN response.

Cerebral malaria (CM) is a life-threatening form of Plasmodium falciparum infection caused by brain inflammation. Brain endothelium dysfunction is a hallmark of CM pathology, which is also associated with the activation of the type I interferon (IFN) inflammatory pathway. The molecular triggers and sensors eliciting brain type I IFN cellular responses during CM remain largely unknown. We herein identified the stimulator of interferon response cGAMP interactor 1 (STING1) as the key innate immune sensor that induces Ifn{beta}1 transcription in the brain of mice infected with Plasmodium berghei (Pba). This STING1/IFN{beta}-mediated response increases brain CXCL10 governing the extent of brain leucocyte infiltration and blood-brain barrier (BBB) breakdown, and determining CM lethality. The critical role of brain endothelial cells (BECs) in fueling type I IFN-driven brain inflammation was demonstrated in brain endothelial-specific IFN{beta}-reporter and STING1-deficient Pba-infected mice, which are significantly protected from CM lethality. Moreover, extracellular particles (EPs) released from Pba-infected erythrocytes activated STING1-dependent type I IFN response in BECs, a response requiring intracellular acidification. Fractionation of the EPs enabled us to identify a defined fraction carrying hemoglobin degradation remnants that activates STING1/IFN{beta} in the brain endothelium, a process correlated with heme content. Notably, stimulation of STING1-deficient BECs with heme, docking experiments and in vitro binding assays unveiled that heme is a putative STING1 ligand. This work shows that heme resultant from the parasite heterotrophic activity operates as an alarmin triggering brain endothelial inflammatory responses via STING1/IFN{beta}/CXCL10 axis crucial to CM pathogenesis and lethality. SignificanceCM results from loss of blood-brain endothelial barrier function caused by unrestrained inflammatory response in the natural course of infection by Plasmodium parasites. However, the role of brain endothelium in triggering inflammatory mechanisms is still undetermined. We found that the innate immune sensor STING1 is crucial for production of IFN{beta} in brain endothelial cells in Plasmodium-infected mice. This in turn stimulates CXCL10-mediated recruitment of leukocytes and subsequent brain inflammation and tissue damage. We identified within extracellular particles released from Plasmodium-infected erythrocytes, a fraction containing products of hemoglobin degradation, namely heme, which we show can bind STING1. Our results unravel a new angle of CM pathogenesis: heme contained in particles triggers the STING/IFN{beta}/CXCL10 axis in brain endothelial cells.

immunology↗

bioRxiv2020

Mycobacterium tuberculosis Rv0991c is a redox-regulated molecular chaperone

The bacterial pathogen Mycobacterium (M.) tuberculosis is the leading cause of death by an infectious disease among humans. Here, we describe a previously uncharacterized M. tuberculosis protein, Rv0991c, as a molecular chaperone that is activated by oxidation. Rv0991c has homologues in most bacterial lineages and appears to function analogously to the well-characterized Escherichia coli redox-regulated chaperone Hsp33, despite a dissimilar protein sequence. Rv0991c is transcriptionally co-regulated with hsp60 and hsp70 chaperone genes in M. tuberculosis, suggesting that Rv0991c functions with these chaperones in maintaining protein quality control. Supporting this hypothesis, we found that, like oxidized Hsp33, oxidized Rv0991c prevents the aggregation of a model unfolded protein in vitro, and promotes its refolding by the M. tuberculosis Hsp70 chaperone system. Furthermore, Rv0991c interacts with DnaK and associates with many other M. tuberculosis proteins. Importantly, we found Rv0991c is required for the full virulence of M. tuberculosis in mice. We therefore propose that Rv0991c, which we named "Ruc" (redox-regulated protein with unstructured C-terminus), represents a founding member of a new chaperone family that protects M. tuberculosis and other species from proteotoxicity during oxidative stress. IMPORTANCEM. tuberculosis infections are responsible for more than one million human deaths per year. Developing effective strategies to combat this disease requires a greater understanding of M. tuberculosis biology. As in all cells, protein quality control is essential for the viability of M. tuberculosis, which likely faces proteome stress within a host. Here, we identify an M. tuberculosis protein, Ruc, that gains chaperone activity upon oxidation. Ruc represents a previously unrecognized family of redox-regulated chaperones found throughout the bacterial super-kingdom. In addition to elucidating the activity of this chaperone, we found that Ruc was required for full M. tuberculosis virulence in mice. This work contributes to a growing appreciation that oxidative stress may provide a particular strain on protein stability in cells, and may likewise play a role in M. tuberculosis pathogenesis.

microbiology↗

bioRxiv2019

Developmental Reactive Oxygen Species Target Histone Methylation to Individualize Stress resistance and Lifespan

A central aspect of aging research concerns the question as to when individuality in lifespan arises and what mechanism(s) promote and potentially manifest individual differences in longevity. We have now discovered that a transient increase in reactive oxygen species (ROS), which occurs naturally during early development in a subpopulation of synchronized Caenorhabditis elegans, sets processes into motion that increase stress resistance, improve redox homeostasis and ultimately prolong lifespan in those animals. We find that these effects are linked to the global ROS-mediated decrease in developmental histone H3K4me3 levels. Studies in HeLa cells confirmed that global H3K4me3 levels are ROS-sensitive, and that depletion of H3K4me3 levels increases stress resistance in mammalian cell cultures. In vitro studies identified the Set1-MML histone methyltransferase as the redox sensitive unit of the H3K4-trimethylating COMPASS complex. Our findings imply a novel link between early-life events, ROS-sensitive epigenetic marks, stress resistance and lifespan.

molecular biology↗

bioRxiv2018

Proximal perimeter encoding in the rat rostral thalamus

Perimeters are an important part of the environment, delimiting its geometry. Here, we investigated how perimeters (vertical walls; vertical drops) affect neuronal responses in the rostral thalamus (the anteromedial and parataenial nuclei in particular). We found neurons whose firing patterns reflected the presence of walls and drops, irrespective of arena shape. Their firing patterns were stable across multiple sleep-wake cycles and were independent of ambient lighting conditions. Thus, rostral thalamic nuclei may participate in spatial representation by encoding the perimeters of environments.

neuroscience↗

bioRxiv2017

A convergent depression vulnerability pathway encoded by emergent spatiotemporal dynamics

Fluctuations in brain local field potential (LFP) oscillations reflect emergent network-level signals that mediate behavior. Cracking the code whereby these LFP oscillations coordinate in time and space (spatiotemporal dynamics) to represent complex behaviors would provide fundamental insights into how the brain signals emotional processes at the network level. Here we use machine learning to integrate LFP activity acquired concurrently from seven cortical and subcortical brain regions into an analytical model that predicts the emergence of depression-related behavioral dysfunction across individual mice subjected to chronic social defeat stress. We uncover a spatiotemporal dynamic network in which activity originates in prefrontal cortex (PFC) and nucleus accumbens (NAc, ventral striatum), relays through amygdala and ventral tegmental area (VTA), and converges in ventral hippocampus (VHip). The activity of this network correlates with acute threat responses and brain-wide cellular firing, and it is enhanced in three independent molecular-, physiological-, and behavioral-based models of depression vulnerability. Finally, we use two antidepressant manipulations to demonstrate that this vulnerability network is biologically distinct from the networks that signal behavioral dysfunction after stress. Thus, corticostriatal to VHip-directed spatiotemporal dynamics organized at the network level are a novel convergent depression vulnerability pathway.

neuroscience↗