Biology subjects

Mitra, T.

Publications and source records attributed to Mitra, T..

9 recordsLinked to original sources

bioRxiv2025

Hyperexcitability in Alzheimers Disease triggers a compensatoryneuroprotective response via TREK1

Alzheimers Disease (AD) is marked by early hippocampal and neocortical accumulation of amyloid-beta 42 oligomers (A{beta}42o), driving neuronal hyperactivity and synaptic dysfunction years before symptom onset. While two-pore domain leak potassium channels like TREK1 are crucial for maintaining the resting membrane potential of neurons and shaping their excitability profile, their role in major neurodegenerative disorders like AD remains unknown. Here, we discover an activity-dependent upregulation of TREK1 in AD transgenic mice (3xTg and APP/PS1) and cultured hippocampal/cortical neurons, triggered by A{beta}42o -induced hyperactivity. Mechanistically, we show that increased intracellular calcium activates adenylate cyclase 1/8 (AC1/8), initiating a cAMP-PKA signaling cascade that enhances the expression of chromatin regulator CTCF. This increased CTCF in turn enhances the expression of TREK1 both in vitro and in AD transgenic mice. Through a combination of calcium imaging, patch-clamp electrophysiology, immunostaining, and cognitive assays in a hippocampal TREK1 knockdown AD model, we establish that the pathology-associated upregulation of TREK1 constitutes a critical homeostatic brake on neuronal hyperexcitability. This neuronal response is essential for limiting A{beta}42o-mediated synaptic pathology and delaying cognitive decline. Our study identifies a multi-step signaling cascade triggered by A{beta}42o leading to upregulation of TREK1 that functions as an essential compensatory mechanism for neuronal survival in early AD. This study deciphers a cellular mechanism responsible for the preclinical phase of AD characterized by silent buildup of pathology.

neuroscience↗

bioRxiv2025

Mixed-mobility supported lipid bilayers reveal the modulatory role ofimmobilized ICAM1 on T cell activation, effector functions and immune synapse organization

The immunological synapse (IS) integrates antigen recognition and adhesion to control T cell activation and effector functions. Reductionist systems have been instrumental in dissecting IS organization, but conventional systems constrain all ligands to be either mobile or immobile, unlike antigen-presenting cells where intercellular adhesion molecule 1 (ICAM1) is cytoskeletally anchored while T cell receptor (TCR) ligands remain mobile. Here, we establish mixed-mobility supported lipid bilayers (SLBs) that simultaneously present mobile TCR agonists and immobile ICAM1. Selective immobilization of ICAM1 disrupts centripetal F-actin flow, prevents centralization of TCR microclusters and shifts signaling to peripheral microclusters. This attenuates TCR downregulation through ectocytosis while maintaining recycling, and enhances integrin mechanotransduction, reflected in increased phosphorylation of Focal Adhesion Kinase, Paxillin and the stretch-sensitive adaptor CasL. Functionally, immobilized ICAM1 augments T cell activation, degranulation, Perforin release and cytotoxicity. Importantly, these findings were recapitulated in a cell-cell system engineered to express either full-length, cytoskeleton-anchored ICAM1 or a truncated form lacking cytoskeletal association, with full-length ICAM1 consistently promoting stronger effector responses. These findings identify ligand mobility as a key biophysical parameter that shapes IS organization and T cell effector responses and establish mixed-mobility SLBs as a powerful tool for probing receptor mechanics in immunity.

immunology↗

bioRxiv2025

Membrane Interfacial Potential Governs Surface Condensation andFibrillation of α-Synuclein in Neurons

Biomolecular condensates formed via liquid-liquid phase separation (LLPS) are essential for cellular organization. -Synuclein, an amyloidogenic protein linked to Parkinsons Disease (PD), undergoes phase separation at high concentrations, but the influence of lipid membranes on this process remains unclear. Here, combining in vitro reconstitution, cell biology, and simulations, we show that membranous interfaces promote -Synuclein condensation at physiologically relevant sub-critical concentrations ([~]10 nM) without crowding agents. Notably, condensation occurs only on membranes with a specific stoichiometry of lipids, underscoring the role of interfacial potential. These condensates serve as nucleation sites for fibril formation, leading to membrane deformation and rupture. A lattice gas model reveals this behavior as a prewetting-like transition, where an attractive membrane induces local phase separation below the bulk saturation concentration. Indeed altering interfacial potential by lipid composition and membrane depolarization not only drastically changes -Synuclein puncta size and number but also triggers their release from neurons. These findings reveal the crucial role of lipid membrane interfaces in regulating -Synuclein condensation, aggregation and release, shedding light on a potential mechanism of their cell-to-cell propagation during neurodegeneration.

biophysics↗

bioRxiv2025

MEK-dependent bioenergetic demand drives terminal CD8+ T cell exhaustion

Loss of mitochondrial function contributes to CD8+ T cell dysfunction during persistent antigen encounter. How chronic antigen leads to this metabolic dysfunction remains unclear. Here, we show that TCR-dependent mitochondrial NADH accumulation drives production of ROS, ultimately leading to mitochondrial dysfunction. Among TCR-dependent proximal signaling components, MEK inhibition uniquely reduced nutrient uptake and mitochondrial NADH accumulation while increasing proliferation. As a result, MEK inhibition during chronic TCR stimulation reduced terminal T cell exhaustion. Mechanistically, we found that chronic MEK activation in T cells drove ATP demand by increasing global protein synthesis rates in vitro and in vivo. MEK inhibition reversed chronic TCR stimulation-driven increases in RNA polymerase II CTD phosphorylation, reducing transcription rates at effector- and terminal-exhaustion associated genes while maintaining transcription of memory-associated genes. These findings establish MEK-dependent metabolic demand as a driver of T cell exhaustion and elucidate the role of MEK inhibition in enhancing immunotherapy efficacy.

immunology↗

bioRxiv2023

Suppressive might of a few: T follicular regulatory cells impede auto-reactivity despite being outnumbered in the germinal centres

The selection of high-affinity B cells and the production of high-affinity antibodies are mediated by T follicular helper cells (Tfhs) within germinal centres (GCs). Therein, somatic hypermutation and selection enhance B cell affinity but risk the emergence of self-reactive B cell clones. Despite being outnumbered compared to their helper counterpart, the ablation of T follicular regulatory cells (Tfrs) results in enhanced dissemination of self-reactive antibody-secreting cells (ASCs). The specific mechanisms by which Tfrs exert their regulatory action on self-reactive B cells are largely unknown. We developed computer simulations to investigate how Tfrs regulate either selection or differentiation of B cells to prevent auto-reactivity. We observed that Tfr-induced apoptosis of self-reactive B cells during the selection phase impedes self-reactivity with physiological Tfr numbers, especially when Tfrs can access centrocyte-enriched GC areas. While this aided in selecting non-self-reactive B cells by restraining competition, higher Tfr numbers distracted non-self-reactive B cells from receiving survival signals from Tfhs. Thus, the location and number of Tfrs must be regulated to circumvent such Tfr distraction and avoid disrupting GC evolution. In contrast, when Tfrs regulate differentiation of selected centrocytes by promoting recycling to the dark zone phenotype of self-reactive GC resident pre-plasma cells (GCPCs), higher Tfr numbers were required to impede the circulation of self-reactive ASCs (s-ASCs). On the other hand, Tfr-engagement with GCPCs and subsequent apoptosis of s-ASCs can control self-reactivity with low Tfr numbers, but does not confer selection advantage to non-self-reactive B cells. The simulations predict that to restrict auto-reactivity, natural redemption of self-reactive B cells is insufficient and that Tfrs should increase the mutation probability of self-reactive B cells.

immunology↗

bioRxiv2022

Amount of antigen, T follicular helper cells and quality of seeder cells shape the diversity of germinal center B cells

A variety of B cell clones seed the germinal centers, where a selection stringency expands the fitter clones to generate higher affinity antibodies. However, recent experiments suggest that germinal centers often retain a diverse set of B cell clones with a range of affinities and concurrently carry out affinity maturation. Amid a tendency to flourish germinal centers with fitter clones, how several B cell clones with differing affinities can be concurrently selected remains poorly understood. Such a permissive selection may allow non-immunodominant clones, which are often rare and of low-affinity, to somatically hypermutate and result in a broad and diverse B cell response. How the constituent elements of germinal centers, their quantity and kinetics may modulate diversity of B cells, has not been addressed well. By implementing a state-of-the-art agent-based model of germinal center, here, we study how these factors impact temporal evolution of B cell clonal diversity and its underlying balance with affinity maturation. While we find that the extent of selection stringency dictates clonal dominance, limited antigen availability on follicular dendritic cells is shown to expedite the loss of diversity of B cells as germinal centers mature. Intriguingly, the emergence of a diverse set of germinal center B cells depends on high affinity founder cells. Our analysis also reveals a substantial number of T follicular helper cells to be essential in balancing affinity maturation with clonal diversity, as a low number of T follicular helper cells impedes affinity maturation and also contracts the scope for a diverse B cell response. Our results have implications for eliciting antibody responses to non-immunodominant specificities of the pathogens by controlling the regulators of the germinal center reaction, thereby pivoting a way for vaccine development to generate broadly protective antibodies.

immunology↗

bioRxiv2020

Brain geometry matters in Alzheimer disease progression: a simulation study

The Amyloid cascade hypothesis (ACH) for Alzheimers disease (AD) is modeled over the whole brain tissue with a set of partial differential equations. Our results show that the amyloid plaque formation is critically dependent on the secretion rate of amyloid {beta} (A{beta}), which is proportional to the product of neural density and neural activity. Neural atrophy is similarly related to the secretion rate of A{beta}. Due to a heterogeneous distribution of neural density and brain activity throughout the brain, amyloid plaque formation and neural death occurs heterogeneously in the brain. The geometry of the brain and microglia migration in the parenchyma bring more complexity into the system and result in a diverse amyloidosis and dementia pattern of different brain regions. Although the pattern of amyloidosis in the brain cortex from in-silico results is similar to experimental autopsy findings, they mismatch at the central regions of the brain, suggesting that ACH is not able to explain the whole course of AD without considering other factors, such as tau-protein aggregation or neuroinflammation.

systems biology↗

bioRxiv2019

Mathematical model shows how sleep may affect amyloid β fibrillization

Deposition of amyloid {beta} (A{beta}) fibers in extra-cellular matrix of the brain is a ubiquitous feature associated with several neurodegenerative disorders, especially Alzheimers disease (AD). While many of the biological aspects that contribute to the formation of A{beta} plaques are well addressed at the intra- and inter-cellular level in short timescales, an understanding of how A{beta} fibrillization usually starts to dominate at a longer timescale in spite of the presence of mechanisms dedicated to A{beta} clearance, is still lacking. Furthermore, no existing mathematical model integrates the impact of diurnal neural activity as emanated from circadian regulation to predict disease progression due to a disruption in sleep-wake cycle. In this study, we develop a minimal model of A{beta} fibrillization to investigate the onset of AD over a long time-scale. Our results suggest that the diseased state is a manifestation of a phase change of the system from soluble A{beta} (sA{beta}) to fibrillar A{beta} (fA{beta}) domination upon surpassing a threshold in the production rate of soluble A{beta}. By incorporating the circadian rhythm into our model, we reveal that fA{beta} accumulation is crucially dependent on the regulation of sleep-wake cycle, thereby indicating the importance of a good sleep hygiene in averting AD onset. We also discuss potential intervention schemes to reduce fA{beta} accumulation in the brain by modification of the critical sA{beta} production rate.

systems biology↗

bioRxiv2018

Emergent memory in cell signaling: Persistent adaptive dynamics in cascades can arise from the diversity of relaxation time-scales

The mitogen-activated protein kinase (MAPK) signaling cascade, an evolutionarily conserved motif present in all eukaryotic cells, is involved in coordinating critical cell-fate decisions, regulating protein synthesis, and mediating learning and memory. While the steady-state behavior of the pathway stimulated by a time-invariant signal is relatively well-understood, we show using a computational model that it exhibits a rich repertoire of transient adaptive responses to changes in stimuli. When the signal is switched on, the response is characterized by long-lived modulations in frequency as well as amplitude. On withdrawing the stimulus, the activity decays over timescales much longer than that of phosphorylation-dephosphorylation processes, exhibiting reverberations characterized by repeated spiking in the activated MAPK concentration. The long-term persistence of such post-stimulus activity suggests that the cascade retains memory of the signal for a significant duration following its removal, even in the absence of any explicit feedback or cross-talk with other pathways. We find that the molecular mechanism underlying this behavior is related to the existence of distinct relaxation rates for the different cascade components. This results in the imbalance of fluxes between different layers of the cascade, with the repeated reuse of activated kinases as enzymes when they are released from sequestration in complexes leading to one or more spike events following the removal of the stimulus. The persistent adaptive response reported here, indicative of a cellular \"short-term\" memory, suggests that this ubiquitous signaling pathway plays an even more central role in information processing by eukaryotic cells.

cell biology↗