Biology subjects

Martirosyan, A.

Publications and source records attributed to Martirosyan, A..

9 recordsLinked to original sources

bioRxiv2024

Ultraviolet B acts as a dietary restriction mimetic by targeting mitochondrial bioenergetics.

Ultraviolet (UV) light is a common environmental stimulus, and UV exposure confers health benefits, with cellular targets still unclear. Here, we show that ultraviolet B (UVB) exposure alters mitochondrial bioenergetics in C. elegans and human skin fibroblasts triggering loss of membrane potential, mitochondrial fission and calcium release. This initial stress is followed by a recovery process relying on mitochondrial biogenesis and fusion, which prevents lasting mitochondrial damage. Strikingly, the transient decline of ATP synthesis caused by UVB-induced mitochondrial changes triggers a swift metabolic re-wiring response that resembles effects of dietary restriction (DR) at the organismal and molecular levels. Both recovery from UVB and DR-mimetic UVB effects require mitochondrial fusion, and we found that dysfunction of fusion during aging abrogates UVB benefits and sensitizes old nematodes to UVB toxicity. Finally, UVB irradiation of the skin was effective in inducing organismal fasting-like phenomena in proof-of-concept tests in young mice. We thus uncovered a novel evolutionary conserved cellular mechanism connecting UV light and metabolism. Our findings illuminate potential DR-mimetic properties of UVB and explain late life-specific UVB intolerance.

cell biology↗

bioRxiv2023

Thalamic nuclei in primary trigeminal neuralgia: gray matter volume patterns before and after surgery

Trigeminal neuralgia is a prevalent chronic pain disorder characterized by recurring episodes of intense facial pain, which significantly impairs patients quality of life. MRI-based biomarkers have consistently demonstrated their ability to predict pain intensity and treatment outcomes. However, most studies have primarily focused on the trigeminal system, paying less attention to the extensive neural reorganization that occurs throughout the brain in response to chronic pain. In this study, we aimed to examine the thalamus, a key brain structure involved in information processing, and provide a detailed perspective on thalamic remodeling in response to chronic pain at the level of individual thalamic nuclei. We analyzed a sample of 62 patients with primary trigeminal neuralgia undergoing surgical treatment, along with 28 healthy participants. Our results revealed significant gray matter volume changes in thalamic nuclei among patients with trigeminal neuralgia. Notably, the intralaminar nuclei (centromedian/parafascicular) and nuclei associated with visual and auditory signal processing (lateral and medial geniculate bodies) exhibited significant alterations, contrasting with the ventral group nuclei involved in nociceptive processing. Additionally, we found no substantial volume increase in any of the studied nuclei following successful surgical intervention 6 months later. The volumes of thalamic nuclei were negatively correlated with pain intensity and disease duration. The findings obtained in this study, albeit preliminary, have promising clinical implications as they unveil previously unknown facets of chronic pain development. PerspectiveThe study examined alterations in gray matter volume within the thalamus of patients diagnosed with trigeminal neuralgia at the level of specific nuclei. The most significant changes were observed in the lateral and medial geniculate bodies, along with the pulvinar nuclei. HighlightsO_LIA detailed investigation of the thalamic nuclei in patients suffering from primary trigeminal neuralgia (TN) has been carried out for the first time. C_LIO_LIPatients with TN showed a significant gray matter volume decrease in intralaminar, sensory and associative nuclei. C_LIO_LIFollowing successful surgery, there was no observed increase in the volume of the investigated nuclei. C_LI

neuroscience↗

bioRxiv2023

Traumatic brain injury modifies adult hippocampal neural stem cell fate to promote neurogenesis at the cost of astrogliogenesis.

Moderate Traumatic brain injury (TBI) can result in long-lasting changes in brain function. Although frequently spared from the acute primary injury, the hippocampus becomes affected during a secondary phase that takes place hours, or even days, after TBI, contributing to cognitive deficits. The hippocampus is one of the few brain areas in the adult brain harboring native neural stem cells (NSCs) that continue to generate new neurons (neurogenesis), and to a lesser extent new astrocytes (astrogliogenesis). While deregulation of hippocampal NSCs and neurogenesis have been observed after TBI, very little is known about how TBI may affect hippocampal astrogliogenesis. Here, we aimed to assess how TBI affects hippocampal NSCs and their subsequent commitment to the neuronal or astroglial lineages. Using a controlled cortical impact model of TBI, single cell RNA sequencing and spatial transcriptomics, we observed a cell population-specific increase in NSC-derived neuronal cells and a decrease in NSC-derived astrocytic cells. These cellular changes were associated with cell-population specific changes in gene expression and dysplasia within the dentate gyrus. Overall, our findings support the conclusion that TBI modifies adult hippocampal NSC fate to promote neurogenesis at the cost of astrogliogenesis, and highlights specific cell populations as possible targets to counteract the changes induced by TBI in the hippocampus.

neuroscience↗

bioRxiv2023

Unravelling cell type specific response to Parkinson's Disease at single cell resolution

Parkinsons Disease (PD) is the second most common neurodegenerative disorder and is generally characterized by impaired motor functions. It currently affects 6.3 million people aged 60 years and more, worldwide. The pathological hallmarks of PD are Lewy bodies (abnormal aggregation of -synuclein inside cells), which are observed primarily in the substantia nigra (SN) region of the midbrain. It is yet not known how different cell types in SN respond during PD and what are the molecular mechanisms underlying neurodegeneration. To address this question, we generated a large-scale single cell transcriptomics dataset from human post-mortem SN tissue of 29 donors including 15 sporadic cases and 14 controls. We obtained data for a total of [~]80K nuclei, representing major cell types of the brain (including neurons, astrocytes, microglia and oligodendrocytes). Pathway and differential gene expression analysis revealed multicellular character of PD pathology involving major cellular response from neuronal and glial cells.

bioinformatics↗

bioRxiv2022

Single-nucleus co-expression networks of dopaminergic neurons support iron accumulation as a plausible explanation to their vulnerability in Parkinson's disease

Motivationgene co-expression networks have been widely applied to identify critical genes and pathways for neurodegenerative diseases such as Parkinsons and Alzheimers disease. Now, with the advent of single-cell RNA-sequencing, we have the opportunity to create cell-type specific gene co-expression networks. However, single-cell RNA-sequencing data is characterized by its sparsity, amongst some other issues raised by this new type of data. ResultsWe present scCoExpNets, a framework for the discovery and analysis of cell-type specific gene coexpression networks (GCNs) from single-cell RNA-seq data. We propose a new strategy to address the problem of sparsity, named iterative pseudo-cell identification. It consists of adding the gene expression of pairs of cells that belong to the same individual and the same cell-type while the number of cells is over 200, thus creating multiple matrices and multiple scGCNs for the same cell-type, all of them seen as alternative and complementary views of the same phenomena. We applied this new tool on a snRNA-seq dataset human post-mortem substantia nigra pars compacta tissue of 13 controls and 14 Parkinsons disease (PD) cases (18 males and 9 females) with 30-99 years. We show that one of the hypotheses that support the selective vulnerability of dopaminergic neurons in PD, the iron accumulation, is sustained in our dopaminergic neurons network models. Moreover, after successive pseudo-celluling iterations, the gene groups sustaining this hypothesis remain intact. At the same time, this pseudo-celulling strategy also allows us to discover genes whose grouping changes considerably throughout the iterations and provides new insights. Finally, since some of our models were correlated with diagnosis and age at the same time, we also developed our own framework to create covariate-specific GCNs, called CovCoExpNets. We applied this new software to our snRNA-seq dataset and we identified 11 age-specific genes and 5 diagnosis-specific genes which do not overlap. Availability and implementationThe CoExpNets implementations are available as R packages: scCoExpNets for creating single-cell GCNs and CovCoExpNets for creating covariate-specific GCNs. Users can either download the development version via github https://github.com/aliciagp/scCoExpNets and https://github.com/aliciagp/CovCoExpNets Contactalicia.gomez1@um.es Supplementary informationsupplementary data is available online.

bioinformatics↗

bioRxiv2022

Molecular and cognitive signatures of ageing partially restored through synthetic delivery of IL2 to the brain

Cognitive decline is a common pathological outcome during aging, with an ill-defined cellular or molecular basis. Among the cellular changes observed with age are alterations to neuronal plasticity, changes in the glial compartment and the decline of the neurogenic niche. In the recent years, the concept of inflammaging, defined as a low-grade inflammation increasing with age, has emerged as a nexus for age-related diseases. This increase of basal inflammation is also observed in the central nervous system. While not classically considered a neurological cell type, infiltrating T cells increase in the brain with age, and may be responsible for amplification of inflammatory cascades and disruptions to the neurogenic niche. Recently, a small resident population of regulatory T cells has been identified in the brain, and the capacity of IL2-mediated expansion of this population to counter neuroinflammatory disease has been demonstrated. Here we test a brain-specific IL2 delivery system for the prevention of neurological decline in aging mice. We identify the molecular hallmarks of aging in the brain glial compartments, and identify partial restoration of this signature through IL2 treatment. At a behavioral level, brain IL2 delivery prevented the age-induced defect in spatial learning, without improving the general decline in motor skill or arousal. These results identify immune modulation as a potential path to preserving cognitive function for healthy ageing.

neuroscience↗

bioRxiv2019

Late life metformin treatment limits cell survival and shortens lifespan by triggering an aging-associated failure of energy metabolism.

The diabetes drug metformin is to be clinically tested in aged humans to achieve health span extension, but little is known about responses of old non-diabetic individuals to this drug. By in vitro and in vivo tests we found that metformin shortens life span and limits cell survival when provided in late life, contrary to its positive early life effects. Mechanistically, metformin exacerbates aging-associated mitochondrial dysfunction towards respiratory failure, aggravated by the inability of old cells to upregulate glycolysis in response to metformin, leading to ATP exhaustion. The beneficial dietary restriction effect of metformin on lipid reserves is abrogated in old animals, contributing to metabolic failure, while ectopic stabilization of cellular ATP levels alleviates late life metformin toxicity in vitro and in vivo. The toxicity is also suspended in nematodes carrying diabetes-like insulin receptor insufficiency and showing prolonged resilience to metabolic stress induced by metformin. In sum, we uncovered an alarming metabolic decay triggered by metformin in late life which may limit its benefits for non-diabetic elderly patients. Novel regulators of life extension by metformin are also presented. HighlightsO_LILate life metformin treatment limits cell survival and shortens lifespan. C_LIO_LIMetformin exacerbates aging-associated mitochondrial dysfunction causing fatal ATP exhaustion. C_LIO_LIOld cells fail to upregulate glycolysis as a compensatory response to metformin. C_LIO_LIThe dietary restriction (DR) mimetic response to metformin is abrogated in old animals. C_LIO_LIPKA and not AMPK pathway instigates the early life DR response to metformin. C_LIO_LIStabilization of cellular ATP levels alleviates late life metformin toxicity in vitro and in vivo. C_LI

physiology↗

bioRxiv2018

Molecularly distinct astrocyte subpopulations spatially pattern the adult mouse brain

Astrocytes are a numerous cell type of the central nervous system. They perform many important functions in synapse formation and maintenance, control of local homeostasis and modulation of synaptic transmission. However, the degree to which specialist astrocyte subtypes fulfil these specific tasks is currently unclear. Here we use single cell transcriptomics to demonstrate that astrocytes, even those lying within the same region of adult mouse brain, show distinct molecular and spatial profiles, with profound implications for local CNS functions, including axon guidance, synaptogenesis and synaptic transmission.

neuroscience↗

bioRxiv2017

Translating ceRNA susceptibilities into correlation functions

Competition to bind microRNAs induces an effective positive crosstalk between their targets, therefore known as competing endogenous RNAs or ceRNAs. While such an effect is known to play a significant role in specific situations, estimating its strength from data and, experimentally, in physiological conditions appears to be far from simple. Here we show that the susceptibility of ceRNAs to different types of perturbations affecting their competitors (and hence their tendency to crosstalk) can be encoded in quantities as intuitive and as simple to measure as correlation functions. We confirm this scenario by extensive numerical simulations and validate it by re-analyzing PTENs crosstalk pattern from TCGA breast cancer database. These results clarify the links between different quantities used to estimate the intensity of ceRNA crosstalk and provide new keys to analyze transcriptional datasets and effectively probe ceRNA networks in silico.

systems biology↗