Biology subjects

Mucha, M.

Publications and source records attributed to Mucha, M..

5 recordsLinked to original sources

bioRxiv2026

Perineuronal nets in the bed nucleus of stria terminalis mediate stress-induced anxiety behaviour in adult male mice

Anxiety disorders affect an estimated 301.4 million people globally. However, they remain among the most challenging conditions to treat, with only around half of patients reporting a 50% or greater reduction in their symptoms. The discovery of novel and more effective treatments therefore requires a better understanding of the underlying mechanisms of anxiety at both the circuit and cellular levels. Stress induces aberrant changes in neuronal plasticity across brain regions within the anxiety circuitry including the bed nucleus of the stria terminalis (BNST). One mechanism through which synaptic plasticity is regulated is the organisation of perineuronal nets (PNNs), specialised extracellular matrix structures that are highly sensitive to stress. In rodent models, stress is associated with a reduction in PNN number and/or decreased Wisteria floribunda Agglutinin (WFA) labelling in limbic areas. However, the development of PNNs within the BNST and their role in the stress responsiveness remain largely unknown. In the current study we investigated the spatiotemporal development of PNNs within the BNST of male mice, where they first appear at P30 and continue to mature into adulthood, reaching their highest expression at P210 and specifically within the anteromedial BNST. We further showed that stress-induced anxiety is associated with a reduction in PNN number and significant changes to PNN fine structure including increased leakiness in the anteromedial BNST. Most importantly, enzymatic removal of PNNs by chondroitinase ABC in the mouse anteromedial BNST exacerbated behavioural responses to acute stress as demonstrated by increased anxiety-like behaviour. Collectively, these results highlight an indispensable role for PNNs within the anteromedial BNST in mediating a healthy emotional response to psychosocial stress.

neuroscience↗

bioRxiv2025

Spatial dissection of ADC/RPT targets defines therapeutic opportunities inrhabdoid tumors

Rhabdoid tumors (RT) are among the most aggressive pediatric malignancies, characterized by early onset, loss of SWI/SNF complex members (SMARCB1 or SMARCA4), and dismal outcomes despite multimodal therapy. Refractory and relapsing RT remain almost uniformly fatal, and targeted or immune-based approaches have yet to demonstrate clinical benefit. To explore novel therapeutic vulnerabilities, we systematically investigated the expression of clinically actionable surface proteins that could serve as targets for antibody-drug conjugates (ADCs), radiopharmaceutical therapy (RPT), or cellular immunotherapies. Based on large-scale transcriptomic analyses, we prioritized FAP, CXCR4, and IL13RA2 and performed comprehensive protein-level validation by immunohistochemistry in an unprecedented cohort of 60 rhabdoid tumors spanning all molecular subgroups (ATRT-TYR, ATRT-SHH, ATRT-MYC, and eMRT). Integrating these data with spatial and single-nucleus transcriptomic profiling, we identified subgroup- and cell-type-specific expression patterns, including heterogeneous FAP distribution between stromal and tumor compartments and a distinct IL13RA2-positive rhabdoid cell population with melanosomal and stem-like features. These findings define a set of biologically and clinically relevant surface targets in RT and provide a translational blueprint for rational ADC and RPT target discovery in pediatric cancer.

cancer biology↗

bioRxiv2025

AEBP2-Directed H3K27me2 Defines a Specific Vulnerability in EZH2-mutant Lymphoma

The catalytic subunit of Polycomb Repressive Complex 2 (PRC2), EZH2, is recurrently mutated in 25% of diffuse large B-cell lymphomas (DLBCL), causing increased H3K27me3 and decreased H3K27me2 levels. EZH2 inhibitors provide clinical benefit, but resistance frequently develops, highlighting the need for alternative therapeutic targets. Here, we identify the PRC2 accessory protein AEBP2 as a specific genetic dependency in EZH2-mutant DLBCL. While AEBP2 acts through PRC2, its essential role is surprisingly independent of canonical H3K27me3-mediated gene silencing. Instead, AEBP2 functions within a PRC2.2 complex lacking JARID2, using its zinc-finger domains to sample intergenic chromatin to sustain H3K27me2. Notably, loss of AEBP2 or NSD2 caused contrasting changes in intergenic H3K27me2 levels, driving sensitivity or resistance to PRC2 inhibitors, respectively. Our findings identify AEBP2-PRC2.2-maintained intergenic H3K27me2 as a therapeutic vulnerability in EZH2-mutant DLBCL and highlight dysregulated H3K27me2 as an underappreciated form of PRC2 dysfunction in cancer, with important therapeutic implications.

cancer biology↗

bioRxiv2021

The sodium leak channel NALCN encodes the major background sodium ion conductance in murine anterior pituitary cells

The pituitary gland produces and secretes a variety of hormones that are essential to life, such as for the regulation of growth and development, metabolism, reproduction, and the stress response. This is achieved through an intricate signalling interplay between the brain and peripheral feedback signals that shapes pituitary cell excitability by regulating ion channel properties of these cells. In addition, endocrine anterior pituitary cells fire action potentials spontaneously to regulate intracellular calcium ([Ca2+]i) level, an essential signalling conduit for hormonal secretion. To this end, pituitary cells have to critically regulate their resting membrane potential (RMP) close to firing threshold, but the molecular identity of the ionic mechanisms involved remains largely unknown. Here, we revealed that the sodium leak channel NALCN, known to modulate neuronal excitability elsewhere in the brain, acts to regulate excitability in the mouse anterior endocrine pituitary cells. Using viral transduction combined with powerful electrophysiology methods and calcium imaging, we show that NALCN forms the major Na+ leak conductance in these cells, appropriately tuning cellular RMP for sustaining spontaneous firing activity. Genetic interruption of NALCN channel activity drastically hyperpolarised the cells, suppressing firing and ([Ca2+]i) oscillations. Remarkably, we uncover that NALCN conductance formed a very small fraction of the total cell conductance, but yet had a profound impact on pituitary cell excitability. Our results also provide a possible mechanism through which hypothalamic and hormone feedback signals can powerfully affect pituitary activity to influence hormonal function.

physiology↗

bioRxiv2021

Plasmin-mediated cleavage of EphA4 at central amygdala inhibitory synapses controls anxiety

Severe stress can trigger complex behavioural changes such as high anxiety (1). Inhibitory GABA-ergic interneurons in the lateral division of the central amygdala (CEl) control anxiety through feedforward inhibition of their target cells in the medial division (CEm) (2, 3). In particular, PKC{delta}-positive (PKC{delta}+) interneurons in CEl are critical elements of the neuronal circuitry of fear and anxiety (3-5), but the molecular mechanisms they employ are poorly understood. Here, we show that, during stress, GABA-ergic synapses of amygdala PKC{delta}+ interneurons are regulated by a serine protease plasmin. On stress, plasmin cleaves the extracellular portion of the tyrosine kinase receptor EphA4 triggering its dissociation from gephyrin, a postsynaptic GABA-receptor anchoring protein. Dynamic EphA4/gephyrin interaction leads to modification of dendritic spine morphology and synaptic GABA-receptor expression profile. Consistent with the critical role for the plasmin/EphA4/gephyrin signalling axis in anxiogenesis, viral delivery of plasmin-resistant (prEphA4) form of EphA4 into the central amygdala prevents the development of stress-induced anxiety in mice, while the delivery of plasmin-truncated EphA4 (tEphA4) dramatically enhances this effect. Thus, our studies identify a novel, critical molecular cascade regulating GABA-ergic signalling in the central amygdala synapses that allows bidirectional switching of animal behaviour from high to low anxiety states.

neuroscience↗