Biology subjects

Perez-Samartin, A.

Publications and source records attributed to Perez-Samartin, A..

6 recordsLinked to original sources

bioRxiv2024

TAF1-dependent transcriptional dysregulation underlies multiple sclerosis

A major conceptual and clinical challenge in multiple sclerosis (MS) is understanding the mechanisms that drive the central nervous system (CNS)-resident neuroinflammation and neurodegeneration underneath disease progression. Genome-wide association studies (GWAS) have implicated RNA polymerase II (RNAPII) promoter-proximal pausing in oligodendrocyte pathology, but the causal mechanisms remain unclear. Here we find that the C-terminal region of TAF1, a core component of the general transcription factor TFIID, is underdetected in progressive MS brains, which can be explained by endoproteolysis due to extralysosomal cathepsin B (CTSB). Mice lacking the C-terminal TAF1 domain (Taf1d38) exhibit MS-like brain transcriptomic signature, alongside CNS-resident inflammation, progressive demyelination, and motor disability. Mechanistically, C-terminal TAF1 interacts with MS-linked factors that cooperate to regulate RNAPII pausing, particularly affecting oligodendroglial myelination genes. These findings uncover a previously unrecognized transcriptional mechanism underlying MS progression and establish a tractable in vivo model for therapeutic development.

neuroscience↗

bioRxiv2024

Systemic migrations in enucleated cells

Directional locomotion is a fundamental characteristic of many cells with great relevance in essential physiological and human pathological processes. For decades, research efforts have focused on studying specific individual processes and their corresponding biomolecular components involved in cellular locomotion movements. However, the notion that migratory displacements are functionally integrated and regulated at the systemic level has never been recognized. Recently, we have shown that locomotion movements correspond to an emergent systemic behavior which depends on a complex integrated self-organized system carefully regulated at a global cellular level. Here, to study the forces driving the locomotion movement of the cell, and to corroborate the thesis on the systemic character of the cellular migratory responses we have carried out an extensive study of locomotion movements with enucleated cells (cytoplasts) belonging to Amoeba proteus. The migratory behavior of both enucleated and non-enucleated cells has been individually studied in four different scenarios: in absence of stimuli, under a galvanotactic field, in chemotactic gradient, and under very complex conditions such as simultaneous galvanotactic and chemotactic stimuli. All these experimental displacement trajectories, obtained on flat two-dimensional surfaces, have been analyzed using advanced non-linear quantitative approaches. Our results show that both non-enucleated amoebas and cytoplasts display the same complex kind of dynamic structure in their migratory trajectories. The locomotion displacements of enucleated cells are regulated by complex self-organized integrative dynamics, modulated at a global-systemic level which seems to depend on the cooperative interaction of most, if not all, molecular components of cells.

systems biology↗

bioRxiv2024

Forces directing the systemic correlations of cell migration

Directional motility is an essential property of cells. Despite its enormous relevance in many fundamental physiological and pathological processes, how cells control their locomotion movements remains an unresolved question. Here we have addressed the systemic processes driving the directed locomotion of cells. Specifically, we have performed an exhaustive study analyzing the trajectories of 700 individual cells belonging to three different species (Amoeba proteus, Metamoeba leningradensis and Amoeba borokensis) in four different scenarios: in absence of stimuli, under an electric field (galvanotaxis), in a chemotactic gradient (chemotaxis), and under simultaneous galvanotactic and chemotactic stimuli. All movements were analyzed using advanced quantitative tools. The results show that the trajectories are mainly characterized by coherent integrative responses that operate at the global cellular scale. These systemic migratory movements depend on the cooperative non-linear interaction of most, if not all, molecular components of cells. SignificanceCellular migration is a cornerstone issue in many human physiological and pathological processes. For years, the scientific attention has been focused on the individualized study of the diverse molecular parts involved in directional motility; however, locomotion movements have never been regarded as a systemic process that operates at a global cellular scale. In our quantitative experimental analysis essential systemic properties underlying locomotion movements were detected. Such emergent systemic properties are not found specifically in any of the molecular parts, partial mechanisms, or individual processes of the cell. Cellular displacements seem to be regulated by integrative processes operating at systemic level.

systems biology↗

bioRxiv2021

Clemastine induces an impairment in developmental myelination

Abnormalities in myelination are associated to behavioral and cognitive dysfunction in neurodevelopmental psychiatric disorders. Thus, therapies to promote or accelerate myelination could potentially ameliorate symptoms in autism. Clemastine, a histamine H1 antagonist with anticholinergic properties against muscarinic M1 receptor, is the most promising drug with promyelinating properties (Mei et al., 2014). Clemastine penetrates the blood brain barrier efficiently and promotes remyelination in different animal models of neurodegeneration including multiple sclerosis, ischemia and Alzheimers disease. However, its role in myelination during development is unknown. We showed that clemastine treatment during development increase oligodendrocyte differentiation in both white and gray matter. However, despite the increase in the number of oligodendrocytes, conduction velocity of myelinated fibers of corpus callosum decreased in clemastine treated mice. Confocal and electron microscopy showed a reduction in the number of myelinated axons and nodes of Ranvier and a reduction of myelin thickness in corpus callosum. To understand the mechanisms leading to myelin formation impairment in the presence of an excess of myelinating oligodendrocytes, we focused on microglial cells which also express muscarinic M1 receptors. Importantly, the population of CD11c+microglia cells, necessary for myelination, as well as the levels of insulin growth factor-1 decrease in clemastine-treated mice. Altogether, these data suggest that clemastine impact on myelin development is more complex than previously thought and could be dependent on microglia-oligodendrocyte crosstalk. Further studies are needed to clarify the role of microglia cells on developmental myelination.

neuroscience↗

bioRxiv2018

Evidences of conditioned behavior in Amoeba proteus

Associative memory is the main type of learning wherein complex organisms endowed with evolved nervous systems respond efficiently to determined environmental stimuli. This fundamental cognitive property has been evidenced in different multicellular species, from cephalopods to Humans, but never in individual cells. Here, following Pavlovs experiments with dogs that founded the principles of classical conditioning, we have observed the development of an associative memory in Amoeba proteus, which corresponds to the emergence of a new systemic motility pattern. In our cellular version of this conditioning behavior, we have used a controlled direct current electric field as the conditioned stimulus and a specific chemotactic peptide as the non-conditioned stimulus. Our study allowed us to demonstrate that Amoeba proteus are capable of linking two independent past events, and the induced associative memory can be recorded for up to at least four hours. For the first time, it has been observed that a systemic response to a specific stimulus can be modified by learning in unicellular organisms. This finding opens up a new framework in the understanding of the mechanisms underlying the complex systemic behavior involved in the cellular migration and the adaptive capacity of cells to the external medium.

systems biology↗

bioRxiv2017

Long-Term Memory In The Migration Movements Of Enucleated Amoeba proteus

How motile, free unicellular organisms maximize the rate at which they encounter resources and develop optimal search strategies remains largely unknown. In fact, cell foraging is a very complex activity in which unicellular organisms integrate a diversity of external cues and develop efficient systemic movements to localize nourishment. These foraging strategies are critical when cells face conditions of scarce resources or they dont possess information on where food is located. Here, in order to determine whether nuclear activity is directly involved in cell migration, we placed single, well-isolated, enucleated and non-enucleated starved Amoeba proteus on nutrient-free petri dishes, and we then analyzed their trajectories of movement using non-linear dynamic tools. We found that despite being enucleated, the systemic responses of the protoplasm exhibited typical biological behaviors, moving with apparent normality, creeping along the substrate, developing pseudopodia and gobbling up prey. Our quantitative studies show that both the non-enucleated and enucleated amoebas display a similar migration structure, characterized by super-diffusivity, non-trivial long-term correlations and move-step fluctuations with scale invariant properties. In conclusion, the nuclear activity does not seem to directly control the systemic cellular movements involved in locating sparse resources.

systems biology↗