Biology subjects

Wefers, B.

Publications and source records attributed to Wefers, B..

5 recordsLinked to original sources

bioRxiv2026

Ubiquitin ligase RNF126 exerts functions in lysosomal damage response and lysosomal homeostasis maintenance

The response to lysosomal membrane permeabilization involves extensive ubiquitylation at the lysosome; however, the ubiquitin ligases identified so far cannot account for the complexity of the response. Using extensive spatial proteomics, we identified RNF126 as a new ligase that is robustly recruited to lysosomes in response to a range of different damage triggers across distinct cell types. Recruitment is mediated independent of BAG6 via an arginine-rich stretch in the low-complexity region of RNF126 to mostly unacidified lysosomes in the perinuclear region. Ubiquitin remnant mass spectrometry identified several damage-induced RNF126 substrates, among them known lysosomal damage response components and potential new factors that might drive regeneration from lysosomal damage. Consistently, RNF126 deletion resulted in persistent lysosomal swelling. In addition, we uncovered a constitutive role of RNF126 in lysosomal homeostasis maintenance. Hence, our findings identified the ubiquitin ligase RNF126 as novel lysosomal health regulating factor with functions in homeostasis and stress conditions.

cell biology↗

bioRxiv2025

GluTrooper: a novel reporter mouse line for whole-brain imaging of glutamate dynamics

Glutamate is the primary excitatory neurotransmitter in the mammalian brain. However, tools to image glutamate dynamics in the whole brain with high spatial and temporal resolution are lacking. Therefore, we developed GluTrooper, a novel mouse line engineered for inducible and long-lasting expression of the genetically encoded glutamate sensor iGluSnFR3. GluTrooper mice crossed with Emx1-Cre lines demonstrated uniform and stable sensor expression in excitatory neurons of the cortex, hippocampus, and olfactory bulb. iGluSnFR3 expression remained stable for at least 12 months, enabling longitudinal observations of glutamate dynamics over extended periods. Using multimodal imaging in awake mice, we demonstrated the versatility of GluTrooper across multiple spatial scales: from mesoscale widefield cortical imaging to cellular resolution with two-photon microscopy. Moreover, during cortical spreading depolarization, bilateral whole-brain glutamate dynamics and contralateral cortical disinhibition were detected with high fidelity. Accordingly, the GluTrooper may open new avenues for the better understanding of glutamatergic neurotransmission in the mammalian brain.

neuroscience↗

bioRxiv2025

BACE1 regulates sleep-wake cycle through both enzymatic and non-enzymatic actions.

The {beta}-secretase BACE1 has become a prime target in Alzheimers disease (AD) therapy, because it drives the production of pathogenic amyloid {beta} peptides. However, clinical trials with BACE1-targeting drugs were halted due to adverse effects on cognitive performance. We propose here that cognitive impairment by BACE1 inhibitors may be a corollary of a higher function of BACE1 related to proper sleep regulation. To address non-enzymatic effects of BACE1 on ion channels likely involved in the sleep-wake cycle, we analyzed sleep patterns in both BACE1-KO mice and a newly generated transgenic line expressing a proteolysis-deficient BACE1 variant (BACE1-KI). We found that BACE1-KI and BACE1-KO mice displayed common and distinct sleep-wake disturbances. Compared to their respective wild-type littermates, both mutant lines slept less during the light phase (when they preferentially rest). Furthermore, transition rates between wake and sleep states were altered, as were sleep spindles and EEG power spectra mainly in the gamma range. Thus, a better understanding of how BACE1 interferes with sleep-modulated behaviors is needed if clinical trials with BACE1-targeted inhibitors are to resume.

animal behavior and cognition↗

bioRxiv2024

TREM2 expression level is critical for microglial state, metabolic capacity and efficacy of TREM2 agonism

Triggering receptor expressed on myeloid cells 2 (TREM2) is a central regulator of microglial activity and sequence variants are major risk factors for late onset Alzheimers disease (LOAD). To better understand the molecular and functional changes associated with TREM2 signalling, we generated a TREM2 reporter mouse model and observed a gradual upregulation of reporter expression with increasing plaque proximity. Isolated microglia were sorted based on reporter expression and their transcriptomic profiles acquired in both wildtype and APP transgenic animals, allowing us to disentangle TREM2 versus pathology-specific effects. Bulk RNA-sequencing highlighted TREM2 level-dependent changes in major immunometabolic pathways, with enrichment of genes in oxidative phosphorylation and cholesterol metabolism in microglia with increased TREM2 expression. To confirm these findings, we next analysed uptake of fluorodeoxyglucose (FDG) and examined metabolomic and lipidomic profiles. Again, independent of A{beta} pathology, TREM2 expression correlated with uptake of FDG as well as increased cellular redox, energetics, and cholesterol homeostasis. Finally, we performed chronic treatment with a brain penetrant TREM2 agonist and identified a window of TREM2 expression where microglia are most responsive. Thus, our data provide novel insights into TREM2-mediated regulation of microglial metabolic function and informs current efforts to bring TREM2 agonists into clinical application.

neuroscience↗

bioRxiv2020

The Alzheimer's disease-associated protective Plcγ2-P522R variant promotes beneficial microglial functions

BackgroundMicroglia-specific genetic variants are enriched in several neurodegenerative diseases, including Alzheimers disease (AD), implicating a central role for alterations of the innate immune system in the disease etiology. A rare coding variant in the PLCG2 gene (rs72824905, p.P522R) selectively expressed in microglia and macrophages was recently identified and shown to reduce the risk for AD. MethodsTo assess the role of this variant in the context of immune cell functions, we generated a Plc{gamma}2-P522R knock-in (KI) mouse model using CRISPR/Cas9 gene editing. ResultsFunctional analyses of macrophages derived from homozygous KI mice and wild type (WT) littermates revealed that the P522R variant potentiates the primary function of Plc{gamma}2 as a Pip2-metabolizing enzyme. This was associated with improved survival, enhanced phagocytic activity, and increased acute inflammatory response of the KI cells. Enhanced phagocytosis was also observed in mouse BV2 microglia-like cells overexpressing human PLC{gamma}2-P522R, but not in PLC{gamma}2-WT expressing cells. Furthermore, the brain mRNA signature together with microglia-specific PET imaging indicated microglia activation in Plc{gamma}2-P522R KI mice. ConclusionThus, we have delineated cellular mechanisms of the protective Plc{gamma}2-P522R variant, which provide further support for the emerging idea that activated microglia exert protective functions in AD.

neuroscience↗