Biology subjects

Sciortino, A.

Publications and source records attributed to Sciortino, A..

8 recordsLinked to original sources

bioRxiv2025

Transcriptional Dysregulation in the Hippocampus of a murine model for Parkinson's Disease Cognition Impairment is Driven by Sex, Age, and Alpha-synuclein overexpression

Cognitive impairment is the most common and detrimental, but understudied non-motor symptom of Parkinsons disease (PD). Neuropathologically, it is associated with alpha-synuclein (Syn) misfolding and synapse loss in hippocampus and prefrontal cortex, leading to cognition loss and ultimately dementia. The molecular underpinnings of PD-associated cognitive dysfunction are unknown. In the present study, longitudinal gene expression profiling was performed to characterise molecular hippocampal alterations in a transgenic mouse overexpressing E46K mutated Syn, a model of early PD with loss of synaptophysin, a proxy marker of cognition, in hippocampus and cortex. Comparing 4 different ages of mice from both sexes showed that hippocampal gene expression changes were sexually dimorphic and strongly modulated by age and Syn overexpression. Pathways that emerged across different comparisons were connected to a variety of neuronal functions, collagen synthesis/remodelling, cellular stress, and inflammatory responses. The findings indicate that sex and age are essential covariates to consider when studying PD-associated cognitive decline. The uncovering of early events leading to disease in an animal model is an essential step toward prognostic biomarker identification and early interventions, which may have implications for monitoring, and for timing of therapeutic approaches.

neuroscience↗

bioRxiv2025

Filament transport supports contractile steady states of actin networks.

In all eukaryotic cells, the actin cytoskeleton is maintained in a dynamic steady-state. Actin filaments are continuously displaced from cell periphery, where they assemble, towards the cells center, where they disassemble. Despite this constant flow and turnover, cellular networks maintain their overall architecture constant. How such a flow of material can support dynamic yet steady cellular architectures remains an open question. To investigate the role of myosin-based forces in contractile steady-states of actin networks, we used a reconstituted in vitro system based on a minimal set of purified proteins, namely actin, myosin and actin regulators. We found that, contrary to previous bulk experiments, when confined in microwells, the actin network could self-organize into ordered arrangements of contractile bundles, flowing continuously without collapsing. This was supported by three-dimensional fluxes of actin filaments, spatially separated yet balancing each other. Unexpectedly, maintaining these fluxes did not depend on filament nucleation or elongation, but solely on filament transport. Ablation of the contractile bundles abolished the flux balance and led to network collapse. These findings demonstrate that the dynamic steady state of actin networks can be sustained by filament displacement and recirculation, independently of filament assembly and disassembly. Significance StatementCellular structures continuously self-renew, with new material constantly being added and removed while maintaining overall structural stability. This is particularly true for the actin cytoskeleton, whose components are continuously assembled, displaced, and reassembled. Understanding this process is fundamental to uncovering how cells regulate their architecture and adapt to stimuli. Here, we reconstitute an in vitro actomyosin network capable of contracting steadily over time without collapsing, relying solely on myosin-based transport. These findings demonstrate that a minimal system consisting of actin and molecular motors can effectively recapitulate the ability of actin networks to self-organize into stable yet dynamic architectures.

biophysics↗

bioRxiv2024

Cluster Formation and Phase Separation Driven by Mobile Myosin Motors in the Motility Assay

Interactions between F-actin and myosin are critically important for a wide range of biological processes, including cell migration, cytokinesis, and morphogenesis. The motility assay with myosin motors fixed on a surface has been utilized for understanding various phenomena emerging from the interactions between F-actin and myosin. For example, F-actin in the motility assay exhibited distinct collective behaviors when actin concentration was above a critical threshold. Recent studies have performed the myosin motility assay on a lipid bilayer, meaning that myosin motors anchored on the fluid-like membrane have mobility. Interestingly, mobile motors led to very different collective behaviors of F-actin compared to those induced by stationary motors. However, the dynamics and mechanism of the unique collective behaviors have remained elusive. In this study, we employed our cutting-edge computational model to simulate the motility assay with mobile myosin motors. We reproduced the formation of actin clusters observed in experiments and showed that F-actin within clusters exhibits strong polar ordering and leads to phase separation between myosin motors and F-actin. The cluster formation was highly dependent on the average length and concentration of F-actin. Our study provides insights into understanding the collective behaviors of F-actins that could emerge under more physiological conditions.

biophysics↗

bioRxiv2024

Topological Excitations govern Ordering Kinetics in Endothelial Cell Layers

Many physiological processes, such as the shear flow alignment of endothelial cells in the vasculature, depend on the transition of cell layers between disordered and ordered phases. Here, we demonstrate that such a transition is driven by the non-monotonic evolution of nematic topological defects and the emergence of topological strings that bind the defects together, unveiling an intermediate phase of ordering kinetics in biological matter. We used time-resolved large-scale imaging and physical modeling to resolve the nature of the non-monotonic decrease in the number of defect pairs. The interaction of the intrinsic cell layer activity and the alignment field determines the occurrence of defect domains, which defines the nature of the transition. Defect pair annihilation is mediated by topological strings spanning multicellular scales within the cell layer. We propose that these long-range interactions in the intermediate ordering phase have significant implications for a wide range of biological phenomena in morphogenesis, tissue remodeling, and disease progression.

biophysics↗

bioRxiv2024

Park7 deletion leads to age- and sex-specific transcriptome changes involving NRF2-CYP1B1 axis in mouse midbrain astrocytes

AbstractdispeLoss-of-function mutations in PARK7, encoding for DJ-1, can lead to early onset Parkinsons disease (PD). In mice, Park7 deletion leads to dopaminergic deficits during aging, and increased sensitivity to oxidative stress. However, the severity of the reported phenotypes varies. To understand the early molecular changes upon loss of DJ-1, we performed transcriptomic profiling of midbrain sections from young mice. Interestingly, while at 3 months the transcriptomes of both male and female mice were unchanged compared to their wildtype littermates, an extensive deregulation was observed specifically in 8-month-old males. The affected genes are involved in processes such as focal adhesion, extracellular matrix interaction, and epithelial-to-mesenchymal transition (EMT), and enriched for primary target genes of Nuclear factor erythroid 2-related factor 2 (NRF2). Consistently, the antioxidant response was altered specifically in the midbrain of male DJ-1 deficient mice. Many of the misregulated genes are known target genes of estrogen and retinoic acid signaling and show sex-specific expression in wildtype mice. Depletion of DJ-1 or NRF2 in male, but not female primary astrocytes recapitulated many of the in vivo changes, including downregulation of cytochrome P450 family 1 subfamily B member 1 (CYP1B1), an enzyme involved in estrogen and retinoic acid metabolism. Interestingly, knock-down of CYP1B1 led to gene expression changes in focal adhesion and EMT in primary male astrocytes. Finally, male iPSC-derived astrocytes with loss of function mutation in the PARK7 gene also showed changes in the EMT pathway and NRF2 target genes. Taken together, our data indicate that loss of Park7 leads to sex-specific gene expression changes specifically in males through astrocytic alterations in the NRF2-CYP1B1 axis. These findings suggest higher sensitivity of males to loss of DJ-1 and might help to better understand variation in the reported Park7-/-phenotypes.

molecular biology↗

bioRxiv2023

Active membrane deformations of a minimal synthetic cell

Biological cells exhibit the remarkable ability to adapt their shape in response to their environment, a phenomenon that hinges on the intricate interplay between their deformable membrane and the underlying activity of their cytoskeleton. Yet, the precise physical mechanisms of this coupling remain mostly elusive. Here, we introduce a synthetic cell model, comprised of an active cytoskeletal network of microtubules, crosslinkers and molecular motors encapsulated inside giant vesicles. Remarkably, these active vesicles exhibit large shape fluctuations and life-like morphing abilities. Active forces from the encapsulated cytoskeleton give rise to large-scale traveling membrane deformations. Quantitative analysis of membrane and microtubule fluctuations shows how the intricate coupling of confinement, membrane material properties and cytoskeletal forces yields fluctuation spectra whose characteristic scales in space and time are distinctly different from passive vesicles. We demonstrate how activity leads to uneven probability fluxes between fluctuation modes and hence sets the temporal scale of membrane fluctuations. Using simulations and theoretical modelling, we extend the classical approach to membrane fluctuations to active cytoskeleton-driven vesicles, highlighting the effect of correlated activity on the dynamics of membrane deformations and paving the way for quantitative descriptions of the shape-morphing ability typical of living systems.

biophysics↗

bioRxiv2022

Dietary fibre deprivation and bacterial curli exposure shift gut microbiome and exacerbate Parkinson's disease-like pathologies in an alpha-synuclein-overexpressing mouse

The microbiome-gut-brain axis has been proposed as a pathogenic path in Parkinsons disease (PD). Dietary driven dysbiosis and reduced gut barrier function could facilitate the interaction of toxic external or internal factors with the enteric nervous system, where PD could start. Amyloid bacterial protein such as curli can act as seed to corrupt enteric -synuclein and lead to its aggregation. Misfolded -synuclein can propagate to and throughout the brain. Here, we aimed at understanding if fibre deprivation and amyloidogenic protein curli could, individually or together, exacerbate the phenotype in both enteric and central nervous systems of a transgenic mouse overexpressing wild-type human -synuclein. We analysed the gut microbiome, motor behaviour, gastrointestinal and brain pathologies in these mice. Our findings show that external interventions, akin to unhealthy life habits in humans, can exacerbate PD-like pathologies in mice. We believe that our results shed light on how lifestyle affects PD progression.

neuroscience↗

bioRxiv2020

A new synuclein-transgenic mouse model for early Parkinson's reveals molecular features of preclinical disease

Understanding Parkinsons disease (PD) in particular in its earliest phases is important for diagnosis and treatment. However, human brain samples are collected post-mortem, reflecting mainly end stage disease. Because brain samples of mouse models can be collected at any stage of the disease process, they are useful to investigate PD progression. Here, we compare ventral midbrain transcriptomics profiles from -synuclein transgenic mice with a progressive, early PD-like striatum neurodegeneration across different ages using pathway, gene set and network analysis methods. Our study uncovers statistically significant altered genes across ages and between genotypes with known, suspected or unknown function in PD pathogenesis and key pathways associated with disease progression. Among those are genotype-dependent alterations associated with synaptic plasticity, neurotransmission, as well as mitochondria-related genes and dysregulation of lipid metabolism. Age-dependent changes were among others observed in neuronal and synaptic activity, calcium homeostasis, and membrane receptor signaling pathways, many of which linked to G-protein coupled receptors. Most importantly, most changes occurred before neurodegeneration was detected in this model, which points to a sequence of gene expression events that may be relevant for disease initiation and progression. It is tempting to speculate that molecular changes similar to those changes observed in our model happen in midbrain dopaminergic neurons before they start to degenerate. In other words, we believe we have uncovered molecular changes that accompany the progression from preclinical to early PD.

neuroscience↗