Biology subjects

Martinez, A.

Publications and source records attributed to Martinez, A..

97 records · Page 6Linked to original sources

bioRxiv2019

The necroptosis machinery mediates axonal degeneration in a model of Parkinson disease

Parkinsons disease (PD) is the second most common neurodegenerative condition, characterized by motor impairment due to the progressive degeneration of dopaminergic neurons in the substantia nigra and depletion of dopamine release in the striatum. Accumulating evidence suggest that degeneration of axons is an early event in the disease, involving destruction programs that are independent of the survival of the cell soma. Necroptosis, a programmed cell death process, is emerging as a mediator of neuronal loss in models of neurodegenerative diseases. Here, we demonstrate activation of necroptosis in postmortem brain tissue from PD patients and in a toxin-based mouse model of the disease. Inhibition of key components of the necroptotic pathway resulted in a significant delay of 6-hydroxydopamine dependent axonal degeneration of dopaminergic and cortical neurons in vitro. Genetic ablation of necroptosis mediators MLKL and RIPK3, as well as pharmacological inhibition of RIPK1 in vivo, decreased dopaminergic neuron degeneration, improving motor performance. Together, these findings suggest that axonal degeneration in PD is mediated by the necroptosis machinery, a process here referred to as necroaxoptosis, a druggable pathway to target dopaminergic neuronal loss.

neuroscience↗

bioRxiv2018

Comprehensive analysis of tumour initiation, spatial and temporal progression under multiple lines of treatment

Driver mutations alter cells from normal to cancer through several evolutionary epochs: premalignancy, early malignancy, subclonal diversification, metastasis and resistance to therapy. Later stages of disease can be explored through analyzing multiple samples collected longitudinally, on or between successive treatments, and finally at time of autopsy. It is also possible to study earlier stages of cancer development through probabilistic reconstruction of developmental trajectories based on mutational information preserved in the genome. Here we present a suite of tools, called Phylogic N-Dimensional with Timing (PhylogicNDT), that statistically model phylogenetic and evolutionary trajectories based on mutation and copy-number data representing samples taken at single or multiple time points. PhylogicNDT can be used to infer: (i) the order of clonal driver events (including in pre-cancerous stages); (ii) subclonal populations of cells and their phylogenetic relationships; and (iii) cell population dynamics. We demonstrate the use of PhylogicNDT by applying it to whole-exome and whole-genome data of 498 lung adenocarcinoma samples (434 previously available and 64 of newly generated data). We identify significantly different progression trajectories across subtypes of lung adenocarcinoma (EGFR mutant, KRAS mutant, fusion-driven and EGFR/KRAS wild type cancers). In addition, we study the progression of fusion-driven lung cancer in 21 patients by analyzing samples from multiple timepoints during treatment with 1st and next generation tyrosine kinase inhibitors. We characterize their subclonal diversification, dynamics, selection, and changes in mutational signatures and neoantigen load. This methodology will enable a systematic study of tumour initiation, progression and resistance across cancer types and therapies.

bioinformatics↗

bioRxiv2018

Mesenchymal stromal cells release CXCL1/2/8 and induce chemoresistance and macrophage polarization

Factors released by surrounding cells such as cancer-associated mesenchymal stromal cells (CA-MSCs) are involved in tumor progression and chemoresistance. We determine the mechanisms by which a naive MSC could become a CA-MSC and characterize CA-MSCs. Ovarian tumor cells (OTC) trigger the transformation of MSCs to CA-MSCs expressing different pro-tumoral, genes and secreting high amounts of CXCR1/2 ligands (CXCL1, CXCL2 and IL-8) implicated in the chemoresistance of cancer cells. CXCR1/2 ligands can also inhibit the immune response against OTC. Indeed, through their released factors, CA-MSCs can trigger the differentiation of monocytes to pro-tumoral M2 phenotype macrophages known to promote the tumor progression. When CXCR1/2 receptors are inhibited, these CA-MSC-activated macrophages lose their M2 functions and acquire an anti-tumoral phenotype. Both ex vivo and in vivo a CXCR1/2 inhibitor can sensitize OTC to carboplatin even in the presence of a pro-tumoral microenvironment. This inhibitor can circumvent the pro-tumoral effects of CA-MSCs. As high concentrations of CXCR1/2 ligands in blood from patients can be associated with chemoresistance, CXCR1/2 inhibition could be a potential therapeutic strategy to revert chemoresistance.

cancer biology↗

bioRxiv2018

Telomeric dysfunction triggers an unstable growth arrest leading to irreparable genomic lesions and entry into cellular senescence

Replicative senescence is the permanent growth arrest caused by gradual telomere attrition occurring at each round of genome replication. Critically shortened telomeres lose their protective shelterin complex and t-loop structure revealing uncapped chromosome ends that are recognized as DNA double-strand breaks causing a p53-dependent DNA damage response (DDR) towards proliferation arrest. Because telomeres are heterogeneous in length within a single cell, the number of short telomeres necessary for senescence onset remains ill defined. Using controlled Tin2-mediated shelterin inactivation, we show that telomere uncapping is not sufficient to trigger senescence. While uncapping generates expected telomeric DNA damage detection, the associated weak DDR allows a rapid bypass of the primary growth arrest and re-entry into the cell cycle despite dysfunctional telomeres. During the ensuing mitosis, fused telomeres lead to additional DNA breaks and to genomic instability including chromosomes bridges or micronuclei, which sustain a secondary entry into stable growth arrest. The loss of p53 prevented both primary and secondary growth arrest, leading to amplified genomic instablility. Our results support a new multistep model for entry into telomere-mediated replicative senescence in normal cells, which is not directly induced by telomere uncapping, but rather by an amplification of DNA lesions caused by telomere fusions that leads to permanent irreparable genome damage.

cell biology↗

bioRxiv2018

Genome wide association study of body weight, body mass index, adiposity, and fasting glucose in 3,173 outbred rats

Objective Obesity is influenced by genetic and environmental factors. Despite success of human genome wide association studies (GWAS), the specific genes that confer obesity remain largely unknown. The objective of this study was to use outbred rats to identify genetic loci underlying obesity and related morphometric and metabolic traits.Methods We measured obesity-relevant traits including body weight, body length, body mass index, fasting glucose, and retroperitoneal, epididymal, and parametrial fat pad weight in 3,173 male and female adult N/NIH heterogeneous stock (HS) rats across three institutions, providing data for the largest rat GWAS to date. Genetic loci were identified using a linear mixed model that accounted for the complex family relationships of the HS and covariate to account for differences among the three phenotyping centers.Results We identified 32 independent loci, several of which contained only a single gene (e.g. Epha5, Nrg1 and Klhl14) or obvious candidate genes (Adcy3, Prlhr). There were strong phenotypic and genetic correlations among obesity-related traits, and extensive pleiotropy at individual loci.Conclusions These studies demonstrate utility of HS rats for investigating the genetics of obesity related traits across institutions and identify several candidate genes for future functional testing.Competing Interest StatementThe authors have declared no competing interest.View Full Text

genetics↗

bioRxiv2018

The NuA4 acetyltransferase and non-canonical chromatin-associated MRN/ATM activity temporally define senescence-associated secretory programs

Senescent cells display senescence-associated (SA) phenotypic programs such as proliferation arrest (SAPA) and secretory phenotype (SASP), which mediate their impact on tissue homeostasis. Curiously, senescence-inducing persistent DNA double-strand breaks (pDSBs) cause an immediate DNA damage response (DDR) and SAPA, but SASP requires days to develop, suggesting it requires additional molecular events. Here, we show that pDSBs provoke delayed recruitment of MRN/ATM and KAT5/TRRAP (NuA4/Tip60) complexes to global chromatin. This coincided with activating histone marks on up-regulated SASP genes, whereas depletion of these complexes compromised the SASP. Conversely, histone deacetylase inhibition triggered accelerated MRN/ATM/Tip60-dependent SASP without pDSBs, interlacing acetylation and non-canonical DNA damage-independent, low-level DDR activity in SASP maturation. DDR/acetylation regulation of SA programs is preserved in human cancer cells, suggesting novel targets for modifying treatment-induced SA phenotypes. We propose that delayed chromatin recruitment of acetyltransferases cooperates with non-canonical DDR signaling to ensure SASP activation only in the context of senescence, and not in response to a transient DNA damage-induced proliferation arrest.\n\nHIGHLIGHTS (4 MAX, 85 CHARACTERS EACH)-Tip60 complex cooperate with non-canonical DDR activity to trigger paracrine signals\n\n-Low-level chromatin-associated ATM activity is required for the SASP\n\n-The intensity and temporal dynamics of the SASP can be manipulated\n\neTOC blurb (40 words)A temporal ballet between DNA damage response ATM/MRN and NuA4/Tip60 complexes control senescence-associated paracrine signals that are important during aging and cancer therapy, suggesting that DNA damage responses, acetylation, and chromatin remodeling can be exploited to manipulate senescence and benefit health.

cell biology↗

bioRxiv2018

Mapping molecular datasets back to the brain regions they are extracted from: Remembering the native countries of hypothalamic expatriates and refugees

This article, which includes novel unpublished data along with commentary and analysis, focuses on approaches to link transcriptomic, proteomic, and peptidomic datasets mined from brain tissue to the original locations within the brain that they are derived from using digital atlas mapping techniques. We use, as an example, the transcriptomic, proteomic and peptidomic analyses conducted in the mammalian hypothalamus. Following a brief historical overview, we highlight studies that have mined biochemical and molecular information from the hypothalamus and then lay out a strategy for how these data can be linked spatially to the mapped locations in a canonical brain atlas where the data come from, thereby allowing researchers to integrate these data with other datasets across multiple scales. A key methodology that enables atlas-based mapping of extracted datasets - laser-capture microdissection - is discussed in detail, with a view of how this technology is a bridge between systems biology and systems neuroscience.

neuroscience↗