Biology subjects

Dolga, A. M.

Publications and source records attributed to Dolga, A. M..

5 recordsLinked to original sources

bioRxiv2026

Diesel exhaust particles disrupt mouse and human iPSC-derived microglial function and Amyloid-beta clearance in Alzheimer's disease models

Alzheimers disease (AD) is one of the most common neurodegenerative disorders, yet the environmental drivers that accelerate its progression remain poorly defined. Traffic-related air pollution is emerging as a modifiable AD risk factor, but how inhaled particles perturb microglial clearance of amyloid beta (A{beta}) is unknown. Microglia are the principal A{beta}-clearing phagocytes of the brain. Here, we showed that exposure of primary mouse microglia and human induced pluripotent stem cell-derived microglia (iMGLs) to 3-100 {micro}g/mL diesel exhaust particles (DEP) disrupted microglial homeostasis, induced morphological abnormalities, increased reactive oxygen species, impaired lysosomal degradation, and led to a concentration-dependent loss of phagocytic capacity. Importantly, DEP markedly reduces A{beta} uptake in both species. Transcriptomic profiling revealed a DEP-induced, non-canonical state characterized by metabolic reprogramming, broad suppression of inflammatory pathways, antigen-presentation, chemokine, and species-specific remodeling during subsequent A{beta} challenge, including defective chemotaxis, cell cycle, and cytoskeletal signatures. These data show that DEP profoundly alters microglial transcriptional and metabolic states, leading to impaired A{beta} clearance, which could, thereby, further contribute to AD progression.

neuroscience↗

bioRxiv2026

Single-cell, label-free morphology profiling of iPSC-derived microglia reveals dynamic state transitions

In response to environmental and inflammatory cues, microglia adopt diverse morphologies reflecting their functional state. However, characterizing these morphological alterations in human iPSC-derived microglia (iMGLs) remains limited by reliance on fluorescent labeling, endpoint imaging, and coarse categorical classifications (e.g., ramified vs amoeboid states). Here, we developed a label-free pipeline combining live-cell imaging, Cellpose-SAM segmentation, and CellProfiler-based feature extraction to track iMGL morphology at single-cell resolution over time. Applying this framework to a 24-hour time course of LPS and IFN{gamma} co-stimulation revealed rapid and transient morphological remodeling, with responses peaking within 2-4 hours and partially attenuating thereafter. At single-cell resolution, four morphological states captured the major axes of variation, with co-stimulation driving a pronounced redistribution toward a single "Spread state". Extending the analysis to individual inflammatory stimuli (LPS, IFN{gamma}, IL-1{beta}, IL-6, and TNF) revealed graded but overlapping shifts in state composition, with IFN{gamma} inducing the strongest response, whereas IL-1{beta} showed minimal effects. Importantly, state-level changes alone were insufficient to distinguish stimulus-specific responses. Instead, single-cell density mapping revealed distinct occupancy patterns within a shared morphological landscape. In addition, texture complexity provided an independent feature layer that further separated among treatments, indicating that stimulus identity is represented by continuous, high-dimensional morphological features beyond discrete state assignments. Linking morphology to function, IFN{gamma} produced the largest morphological redistribution and was also the only stimulus to significantly elevate intracellular ROS at 24 h, indicating that morphological remodeling and redox activation can be coordinately engaged by specific inflammatory signals. Together, these findings support a model in which microglia respond to inflammatory stimuli by graded occupancy of a continuous morphological landscape, with each stimulus producing a stimulus-specific occupancy pattern that extends beyond discrete state assignments.

neuroscience↗

bioRxiv2023

Inhibitor-based modulation of huntingtin aggregation reduces fibril toxicity

Huntingtons disease (HD) is a neurodegenerative disorder in which mutated fragments of the huntingtin protein (Htt) undergo misfolding and aggregation. Since misfolded and aggregated proteins can cause cellular stress and cytotoxicity, there is an interest in the development of small molecule aggregation inhibitors as potential modulators of HD pathogenesis. Here, we study how a polyphenol modulates the aggregation mechanism of huntingtin exon 1 (HttEx1) even at sub-stoichiometric ratios. Sub-stoichiometric amounts of curcumin impacted the primary and/or secondary nucleation events, extending the pre-aggregation lag phase. Remarkably, the disrupted aggregation process changed both the aggregate structure and its cell metabolic properties. When administered to neuronal cells, the break-through protein aggregates induced a significantly reduced cellular stress compared to aggregates formed in absence of inhibitors. Structural analysis by electron microscopy, small angle X-ray scattering (SAXS), and solid-state NMR spectroscopy identified changes in the fibril structures, probing both the flanking domains that form the fuzzy coat, as well as the fibril core. The biggest changes affected the latter, which we propose to relate to the presence or absence of polyglutamine (polyQ) {beta}-hairpin structures. Our findings highlight multifaceted consequences of small molecule inhibitors that modulate the protein misfolding landscape, with potential implications for treatment strategies in HD and other amyloid disorders.

biophysics↗

bioRxiv2021

Interaction between BID and VDAC1 is required for mitochondrial demise and cell death in neurons

Mitochondrial damage is a key feature of regulated cell death in neurons. In particular, mitochondrial outer membrane permeabilization (MOMP) has been proposed as a starting point for mitochondrial demise upon cellular stress. Potential mechanisms for MOMP presented in the literature include membrane pore formation by Bcl2-family proteins such as BID and BAX, oligomerization of voltage-dependent anion channels (VDACs) and hetero-oligomer formation of these proteins. In our study, we demonstrate a direct interaction between the voltage-dependent anion channel VDAC1 and the pro-apoptotic protein BID in dying neurons both in vitro and in vivo. Binding of BID to VDAC1 affects anion conductance through VDAC1 and is associated with glutamate-induced cell death in cultured neurons and ischemic brain injury. In cultured neurons, reducing VDAC1 expression significantly attenuates BID-induced hallmarks of mitochondrial damage such as mitochondrial fission, declined mitochondrial respiration, increased ROS production, and mitochondrial membrane potential breakdown. Our data highlight a critical role for VDAC1 as a mitochondrial receptor for activated BID, thereby serving as a key decision point between life and death in neurons. One Sentence SummaryVDAC1 interacts with BID to mediate mitochondrial membrane permeabilization and neuronal cell death.

molecular biology↗

bioRxiv2019

Fibroblast-specific genome-scale modelling predicts an imbalance in amino acid metabolism in Refsum disease

Refsum disease is an inborn error of metabolism that is characterised by a defect in peroxisomal -oxidation of the branched-chain fatty acid phytanic acid. The disorder presents with late-onset progressive retinitis pigmentosa and polyneuropathy and can be diagnosed biochemically by elevated levels of phytanic acid in plasma and tissues of patients. To date, no cure exists for Refsum disease, but phytanic acid levels in patients can be reduced by plasmapheresis and a strict diet.\n\nIn this study, we reconstructed a fibroblast-specific genome-scale model based on the recently published, FAD-curated model, based on Recon3D reconstruction. We used transcriptomics (available via GEO database with identifier GSE138379), metabolomics, and proteomics data (available via ProteomeXchange with identifier PXD015518), which we obtained from healthy controls and Refsum disease patient fibroblasts incubated with phytol, a precursor of phytanic acid.\n\nOur model correctly represents the metabolism of phytanic acid and displays fibroblast-specific metabolic functions. Using this model, we investigated the metabolic phenotype of Refsum disease at the genome-scale, and we studied the effect of phytanic acid on cell metabolism. We identified 53 metabolites that were predicted to discriminate between Healthy and Refsum disease patients, several of which with a link to amino acid metabolism. Ultimately, these insights in metabolic changes may provide leads for pathophysiology and therapy.

systems biology↗