Biology subjects

Petrascheck, M.

Publications and source records attributed to Petrascheck, M..

11 recordsLinked to original sources

bioRxiv2026

Atypical tetracyclines promote longevity and ferroptotic neuroprotection via translation attenuation

Preclinical and clinical studies have reported neuroprotective and geroprotective effects of tetracyclines that are independent of their antibiotic activity, but the underlying mechanisms remain unclear. Here, we systematically profile widely used tetracyclines, including impurities and degradation products, and identify translation attenuation as the shared driver of their neuroprotective and longevity-promoting effects, independent of classical tetracycline mechanisms. Instead, we uncover two mechanistically distinct classes of tetracyclines. Mitochondrial-targeting tetracyclines (MitoTets), exemplified by doxycycline, inhibit the mitochondrial ribosome and attenuate cytosolic translation through activation of the Integrated Stress Response (ISR). In contrast, atypical tetracyclines such as 4-epiminocycline and 12-aminominocycline act as cytosolic-targeting tetracyclines (CytoTets), directly inhibiting the cytosolic ribosome, bypassing the ISR, and protecting neurons from ferroptotic cell death. CytoTets are non-antibiotic, brain-penetrant, and neuroprotective in mouse and human neurons, establishing the tetracyclines as a tunable chemical scaffold for selectively targeting translation in aging and neurodegeneration. HighlightsO_LIThe tetracyclines broadly attenuate translation in multiple eukaryotic models C_LIO_LITranslation attenuation results from both ISR-dependent and ISR-independent mechanisms C_LIO_LIDiscovery of atypical, cytosolic targeting tetracyclines (CytoTETs) that protect from ferroptosis ISR-independently C_LIO_LICytoTETs inhibit translation and are neuroprotective in human-derived neurons and mouse hippocampus C_LI

pharmacology and toxicology↗

bioRxiv2025

Nucleosome stability safeguards cell identity, stress resilience and healthy aging

Nucleosomes are the minimal repeating units of chromatin. Their dynamic assembly and disassembly underpins chromatin organization and genome regulation. However, it remains unclear how intrinsic nucleosome stability contributes to higher-level yet fundamental cellular and organismal properties--such as preservation of cell identity, lineage specification, stress resilience and ultimately healthy aging. To address this, we tested the impact of decreased intrinsic nucleosome stability across multiple cell, tissue and organismal models by introducing histone mutants that weaken histone-histone interactions. While nucleosome instability did not broadly alter global chromatin accessibility, DNA damage, cell proliferation or viability, it impaired lineage-specific gene expression programs, altered lineage specification and activated intrinsic inflammatory and stress pathways in a manner reminiscent of aging in mouse tissues and human cells. Consistently, nucleosome instability accelerated the onset of age-associated transcriptional alterations and functional decline in Caenorhabditis elegans and Drosophila melanogaster, and reduced cellular resilience to exogenous perturbations-- including environmental, epigenetic and mitotic stress--in human cells and Saccharomyces cerevisiae. These cross-species findings identify nucleosome stability as an evolutionarily conserved epigenetic safeguard that preserves cell identity and stress resilience and supports organismal function and healthy aging.

genomics↗

bioRxiv2025

PIEZO channels link mechanical forces to uterine contractions in parturition

AbstractMechanical forces are extensively involved in pregnancy and parturition, but their precise roles and mechanisms remain poorly understood. Here, we identify mechanically activated ion channels PIEZO1 and PIEZO2 as key mechanotransducers required for labor progression. Genetic deletion of Piezo1 and Piezo2 in mice resulted in weakened uterine contractions and severe parturition defects. Tissue-specific knockouts revealed that deletion in either the uterus or sensory neurons alone caused modest defects, whereas combined loss significantly impaired labor, demonstrating additive effects. Single-nuclei sequencing showed that loss of PIEZO reduced expression of connexin43 (Gja1), a gap junction protein in uterine smooth muscle cells, suggesting a mechanistic link to impaired contraction. These findings highlight the critical role of PIEZO channels in mechanotransduction during parturition and suggest therapeutic targets for labor dysfunction.

physiology↗

bioRxiv2025

Uncoupling overeating and fat storage by modulation of different serotonergic receptors

Psychotropic drugs such as antipsychotics improve symptoms of psychiatric disorders. However, they are associated with severe metabolic side effects that remodel energy balance, resulting in weight gain and increased food intake (hyperphagia). Here, we compare how antipsychotics and exogenous serotonin induce hyperphagia by remodeling energy balance. We find that the ability of serotonin and antipsychotics to remodel energy balance strictly depends on the serotonergic receptors SER-7 and SER-5, respectively. While both molecules induce hyperphagia, serotonin does so by increasing energy expenditure and reducing fat stores. In contrast, antipsychotics block the inhibitory effect of fat storage on feeding, thereby inducing hyperphagia and increasing fat stores. Thus, it is possible to manipulate energy balance to induce hyperphagia while either increasing or decreasing fat storage. Inactivation of the germline remodels energy balance similar to antipsychotic treatment, promoting hyperphagia while increasing fat storage. Consistent with overlapping mechanisms, antipsychotics are no longer able to remodel energy balance in both C. elegans and mice lacking an intact germline. Thus, our results uncouple overeating from fat storage and show that overeating can be induced by mechanisms that reduce or increase fat stores.

neuroscience↗

bioRxiv2024

Activity-dependent synthesis of Emerin gates neuronal plasticity by regulating proteostasis

Neurons dynamically regulate their proteome in response to sensory input, a key process underlying experience-dependent plasticity. We characterized the visual experience-dependent nascent proteome within a brief, defined time window after stimulation using an optimized metabolic labeling approach. Visual experience induced cell type-specific and age-dependent alterations in the nascent proteome, including proteostasis-related processes. We identified Emerin as the top activity-induced candidate plasticity protein and demonstrated that its rapid activity-induced synthesis is transcription-independent. In contrast to its nuclear localization and function in myocytes, activity-induced neuronal Emerin is abundant in the endoplasmic reticulum and broadly inhibits protein synthesis, including translation regulators and synaptic proteins. Downregulating Emerin shifted the dendritic spine population from predominantly mushroom morphology to filopodia and decreased network connectivity. In mice, decreased Emerin reduced visual response magnitude and impaired visual information processing. Our findings support an experience-dependent feed-forward role for Emerin in temporally gating neuronal plasticity by negatively regulating translation.

neuroscience↗

bioRxiv2024

Multiple Targets, One Goal: Compounding life-extending effects through Polypharmacology

Analysis of lifespan-extending compounds suggested the most effective geroprotectors target multiple biogenic amine receptors. To test this hypothesis, we used graph neural networks to predict such polypharmacological compounds and evaluated them in C. elegans. Over 70% of the selected compounds extended lifespan, with effect sizes in the top 5% compared to the DrugAge database. This reveals that rationally designing polypharmacological compounds enables the design of geroprotectors with exceptional efficacy. Key takeawaysO_LIThe most effective known geroprotectors act by polypharmacological mechanisms. C_LIO_LIGraph neural networks predicted polypharmacological geroprotectors with a hit rate of 70%. C_LIO_LIThe predicted polypharmacological geroprotectors are exceptionally effective. C_LIO_LIThe predicted polypharmacological mechanism was experimentally confirmed. C_LIO_LIRationally designing polypharmacological compounds results in geroprotectors with exceptional efficacy. C_LI

pharmacology and toxicology↗

bioRxiv2022

Proteostasis is differentially modulated by inhibition of translation initiation or elongation

Recent work has revealed an increasingly important role for mRNA translation in maintaining proteostasis. Inhibiting translation protects from various proteostatic insults, including heat, expression of aggregation-prone proteins, or aging. However, multiple studies have come to differing conclusions about the mechanisms underlying the protective effects of translation inhibition. Here, we systematically lower translation either by pharmacologically inhibiting translation initiation or elongation and show that each step activates distinct protective responses in Caenorhabditis elegans. Targeting initiation triggers an HSF-1 dependent mechanism that protects from heat and age-associated protein misfolding but not from proteotoxicity caused by proteasome dysfunction. Conversely, targeting elongation triggers an HSF-1 independent mechanism that protects from heat and proteasome dysfunction but not from age-associated protein aggregation. Furthermore, while inhibiting translation initiation increases lifespan in wild-type worms, inhibiting translation elongation only extends lifespan when the animals exhibit preexisting proteotoxic stress--either as a result of aggregation-prone protein expression or hsf-1 deficiency. Together our findings suggest that organisms evolved complementary mechanisms that the mRNA translation machinery can trigger to restore proteostasis.

biochemistry↗

bioRxiv2020

The landscape of longevity across phylogeny

Lifespan of model organisms can be extended by genetic, dietary and pharmacological interventions, but these effects may be negated by other factors. To understand robustness of longevity interventions within and across species, we analyzed age-dependent mortality of yeast, fruit flies, nematodes and mice subjected to thousands of genetic, pharmacological or dietary interventions, and applied the principles learned to other organisms. Across phylogeny, the accessible space of lifespan distribution functions, the "landscape of longevity", has a distinct structure of a fiber bundle, with individual fibers given by Strehler-Mildvan degeneracy manifolds. Within species, most interventions perturb parameters of survival curves along particular degeneracy manifolds. Transitions across manifolds are difficult to achieve, but they may lead to robust lifespan-modulating effects. Analyses of intraspecific degeneracy manifolds revealed soft bounds on achievable longevity. For humans, this bound is [~]138 years.

systems biology↗

bioRxiv2019

TargetSeeker-MS: A computational method for drug target discovery using protein separation coupled to mass spectrometry

When coupled to mass spectrometry (MS), energetics-based protein separation (EBPS) techniques, such as thermal shift assay, have shown great potential to identify the targets of a drug on a proteome scale. Nevertheless, the computational analyses assessing the confidence of drug target predictions made by these methods have remained rudimentary and significantly differ depending on the protocol used to produce the data. To identify drug targets in datasets produced using different EBPS-MS techniques, we have developed a novel flexible computational approach named TargetSeeker-MS. We showed that TargetSeeker-MS reproducibly identifies known and novel drug targets in C. elegans and HEK293 samples that were treated with the fungicide benomyl and processed using two different EBPS techniques. We also validated a novel benomyl target in vitro. TargetSeeker-MS, which is available online, allows for the confident identification of targets of a drug on a proteome scale, thereby facilitating the evaluation of its clinical viability.

bioinformatics↗

bioRxiv2018

Translation Attenuation by Minocycline Increases Lifespan and Improves Proteostasis in Old Post-Stress-Responsive Organisms

Aging impairs the activation of Stress Signaling Pathways (SSPs), preventing the induction of longevity mechanisms late in life. Here we show that the antibiotic minocycline increases lifespan and reduces protein aggregation even in old, SSP-deficient C. elegans by targeting cytoplasmic ribosomes, preferentially attenuating translation of highly translated mRNAs. In contrast to most other longevity paradigms, minocycline inhibits rather than activates all major SSPs and extends lifespan in mutants deficient in the activation of SSPs, lysosomal or autophagic pathways. We propose that minocycline lowers the concentration of newly synthesized aggregation-prone proteins, resulting in a relative increase in protein-folding capacity without the necessity to induce protein-folding pathways. Our study suggests that in old individuals with incapacitated SSPs or autophagic pathways, pharmacological attenuation of cytoplasmic translation is a promising strategy to reduce protein aggregation. Altogether, it provides a geroprotecive mechanism for the many beneficial effects of tetracyclines in models of neurodegenerative disease.

physiology↗

bioRxiv2017

Computational Analysis of Lifespan Experiment Reproducibility

Independent reproducibility is essential to the generation of scientific knowledge. Optimizing experimental protocols to ensure reproducibility is an important aspect of scientific work. Genetic or pharmacological lifespan extensions are generally small compared to the inherent variability in mean lifespan even in isogenic populations housed under identical conditions. This variability makes reproducible detection of small but real effects experimentally challenging. In this study, we aimed to determine the reproducibility of C. elegans lifespan measurements under ideal conditions, in the absence of methodological errors or environmental or genetic background influences. To accomplish this, we generated a parametric model of C. elegans lifespan based on data collected from 5,026 wild-type N2 animals. We use this model to predict how different experimental practices, effect sizes, number of animals, and how different shapes of survival curves affect the ability to reproduce real longevity effects. We find that the chances of reproducing real but small effects are exceedingly low and would require substantially more animals than are commonly used. Our results indicate that many lifespan studies are underpowered to detect reported changes and that, as a consequence, stochastic variation alone can account for many failures to reproduce longevity results. As a remedy, we provide power of detection tables that can be used as guidelines to plan experiments with statistical power to reliably detect real changes in lifespan and limit spurious false positive results. These considerations will improve best-practices in designing lifespan experiment to increase reproducibility.

physiology↗