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Abel ERASO PICHOT




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11 publication(s) since Janvier 2014:


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The indicated IF have been collected by the Web of Sciences in


12/08/2019 |
Defined neuronal populations drive fatal phenotype in a mouse model of Leigh syndrome.
Bolea I, Gella A, Sanz E, Prada-Dacasa P, Menardy F, Bard AM, Machuca-Marquez P, Eraso-Pichot A, Modol-Caballero G, Navarro X, Kalume F, Quintana A

Abstract:
Mitochondrial deficits in energy production cause untreatable and fatal pathologies known as mitochondrial disease (MD). Central nervous system affectation is critical in Leigh Syndrome (LS), a common MD presentation, leading to motor and respiratory deficits, seizures and premature death. However, only specific neuronal populations are affected. Furthermore, their molecular identity and their contribution to the disease remains unknown. Here, using a mouse model of LS lacking the mitochondrial complex I subunit Ndufs4, we dissect the critical role of genetically-defined neuronal populations in LS progression. Ndufs4 inactivation in Vglut2-expressing glutamatergic neurons leads to decreased neuronal firing, brainstem inflammation, motor and respiratory deficits, and early death. In contrast, Ndufs4 deletion in GABAergic neurons causes basal ganglia inflammation without motor or respiratory involvement, but accompanied by hypothermia and severe epileptic seizures preceding death. These results provide novel insight in the cell type-specific contribution to the pathology, dissecting the underlying cellular mechanisms of MD.




06/05/2019 |
A roadmap to integrate astrocytes into Systems Neuroscience.
Kastanenka KV, Moreno-Bote R, De Pitta M, Perea G, Eraso-Pichot A, Masgrau R, Poskanzer KE, Galea E

Abstract:
Systems neuroscience is still mainly a neuronal field, despite the plethora of evidence supporting the fact that astrocytes modulate local neural circuits, networks, and complex behaviors. In this article, we sought to identify which types of studies are necessary to establish whether astrocytes, beyond their well-documented homeostatic and metabolic functions, perform computations implementing mathematical algorithms that sub-serve coding and higher-brain functions. First, we reviewed Systems-like studies that include astrocytes in order to identify computational operations that these cells may perform, using Ca(2+) transients as their encoding language. The analysis suggests that astrocytes may carry out canonical computations in a time scale of subseconds to seconds in sensory processing, neuromodulation, brain state, memory formation, fear, and complex homeostatic reflexes. Next, we propose a list of actions to gain insight into the outstanding question of which variables are encoded by such computations. The application of statistical analyses based on machine learning, such as dimensionality reduction and decoding in the context of complex behaviors, combined with connectomics of astrocyte-neuronal circuits, is, in our view, fundamental undertakings. We also discuss technical and analytical approaches to study neuronal and astrocytic populations simultaneously, and the inclusion of astrocytes in advanced modeling of neural circuits, as well as in theories currently under exploration such as predictive coding and energy-efficient coding. Clarifying the relationship between astrocytic Ca(2+) and brain coding may represent a leap forward toward novel approaches in the study of astrocytes in health and disease.




08/2018 | Glia   IF 6
GSEA of mouse and human mitochondriomes reveals fatty acid oxidation in astrocytes.
Eraso-Pichot A, Braso-Vives M, Golbano A, Menacho C, Claro E, Galea E, Masgrau R

Abstract:
The prevalent view in neuroenergetics is that glucose is the main brain fuel, with neurons being mostly oxidative and astrocytes glycolytic. Evidence supporting that astrocyte mitochondria are functional has been overlooked. Here we sought to determine what is unique about astrocyte mitochondria by performing unbiased statistical comparisons of the mitochondriome in astrocytes and neurons. Using MitoCarta, a compendium of mitochondrial proteins, together with transcriptomes of mouse neurons and astrocytes, we generated cell-specific databases of nuclear genes encoding for mitochondrion proteins, ranked according to relative expression. Standard and in-house Gene Set Enrichment Analyses (GSEA) of five mouse transcriptomes revealed that genes encoding for enzymes involved in fatty acid oxidation (FAO) and amino acid catabolism are consistently more expressed in astrocytes than in neurons. FAO and oxidative-metabolism-related genes are also up-regulated in human cortical astrocytes versus the whole cortex, and in adult astrocytes versus fetal astrocytes. We thus present the first evidence of FAO in human astrocytes. Further, as shown in vitro, FAO coexists with glycolysis in astrocytes and is inhibited by glutamate. Altogether, these analyses provide arguments against the glucose-centered view of energy metabolism in astrocytes and reveal mitochondria as specialized organelles in these cells.




25/07/2017 | Sci Rep   IF 4
CREB Regulates Distinct Adaptive Transcriptional Programs in Astrocytes and Neurons.
Pardo L, Valor LM, Eraso-Pichot A, Barco A, Golbano A, Hardingham GE, Masgrau R, Galea E

Abstract:
The cyclic AMP response element binding protein (CREB) is a primary hub of activity-driven genetic programs in neurons controlling plasticity, neurogenesis and survival. By contrast, the gene networks coordinated by CREB in astrocytes are unknown despite the fact that the astrocytic CREB is also activity-driven and neuroprotective. Herein we identified the transcriptional programs regulated by CREB in astrocytes as compared to neurons using, as study materials, transcriptome databases of astrocyte exposed to well-known activators of CREB-dependent transcription as well as publicly available transcriptomes of neuronal cultures. Functional CREB signatures were extracted from the transcriptomes using Gene Ontology, adult-brain gene lists generated by Translating Ribosome Affinity Purification (TRAP) and CREB-target gene repositories. We found minimal overlap between CREB signatures in astrocytes and neurons. In astrocytes, the top triad of functions regulated by CREB consists of 'Gene expression', 'Mitochondria', and 'Signalling', while in neurons it is 'Neurotransmission', 'Signalling' and 'Gene expression', the latter two being represented by different genes from those in astrocytes. The newly generated databases will provide a tool to explore novel means whereby CREB impinges on brain functions requiring adaptive, long-lasting changes by coordinating transcriptional cascades in astrocytes.




02/05/2017 | Nat Commun   IF 12.1
Neurons and neuronal activity control gene expression in astrocytes to regulate their development and metabolism.
Hasel P, Dando O, Jiwaji Z, Baxter P, Todd AC, Heron S, Markus NM, McQueen J, Hampton DW, Torvell M, Tiwari SS, McKay S, Eraso-Pichot A, Zorzano A, Masgrau R, Galea E, Chandran S, Wyllie DJA, Simpson TI, Hardingham GE

Abstract:
The influence that neurons exert on astrocytic function is poorly understood. To investigate this, we first developed a system combining cortical neurons and astrocytes from closely related species, followed by RNA-seq and in silico species separation. This approach uncovers a wide programme of neuron-induced astrocytic gene expression, involving Notch signalling, which drives and maintains astrocytic maturity and neurotransmitter uptake function, is conserved in human development, and is disrupted by neurodegeneration. Separately, hundreds of astrocytic genes are acutely regulated by synaptic activity via mechanisms involving cAMP/PKA-dependent CREB activation. This includes the coordinated activity-dependent upregulation of major astrocytic components of the astrocyte-neuron lactate shuttle, leading to a CREB-dependent increase in astrocytic glucose metabolism and elevated lactate export. Moreover, the groups of astrocytic genes induced by neurons or neuronal activity both show age-dependent decline in humans. Thus, neurons and neuronal activity regulate the astrocytic transcriptome with the potential to shape astrocyte-neuron metabolic cooperation.




03/2017 | Cell Mol Life Sci   IF 6.5
CREB decreases astrocytic excitability by modifying subcellular calcium fluxes via the sigma-1 receptor.
Eraso-Pichot A, Larramona-Arcas R, Vicario-Orri E, Villalonga R, Pardo L, Galea E, Masgrau R

Abstract:
Astrocytic excitability relies on cytosolic calcium increases as a key mechanism, whereby astrocytes contribute to synaptic transmission and hence learning and memory. While it is a cornerstone of neurosciences that experiences are remembered, because transmitters activate gene expression in neurons, long-term adaptive astrocyte plasticity has not been described. Here, we investigated whether the transcription factor CREB mediates adaptive plasticity-like phenomena in astrocytes. We found that activation of CREB-dependent transcription reduced the calcium responses induced by ATP, noradrenaline, or endothelin-1. As to the mechanism, expression of VP16-CREB, a constitutively active CREB mutant, had no effect on basal cytosolic calcium levels, extracellular calcium entry, or calcium mobilization from lysosomal-related acidic stores. Rather, VP16-CREB upregulated sigma-1 receptor expression thereby increasing the release of calcium from the endoplasmic reticulum and its uptake by mitochondria. Sigma-1 receptor was also upregulated in vivo upon VP16-CREB expression in astrocytes. We conclude that CREB decreases astrocyte responsiveness by increasing calcium signalling at the endoplasmic reticulum-mitochondria interface, which might be an astrocyte-based form of long-term depression.




23/02/2015 | Antioxid Redox Signal   IF 6.3
Physiological Control of Nitric Oxide on neuronal BACE1 Translation by Heme-Regulated Eif2-alpha Kinase HRI Induces Synaptogenesis.
Ill-Raga G, Tajes M, Busquets-Garcia A, Ramos-Fernandez E, Vargas LM, Bosch-Morato M, Guivernau B, Valls-Comamala V, Eraso-Pichot A, Guix FX, Fandos C, Rosen MD, Rabinowitz MH, Maldonado R, Alvarez AR, Ozaita A, Munoz FJ

Abstract:
Aims: Hippocampus is the brain center for memory formation, a process that requires synaptogenesis. However hippocampus is dramatically compromised in Alzheimer's disease due to the accumulation of amyloid alpha-peptide, whose production is initiated by BACE1. It is known that pathological stressors activate BACE1 translation through the phosphorylation of the eukaryotic initiation factor-2alpha (eIF2alpha) by GCN2, PERK or PKR kinases leading to amyloidogenesis. However BACE1 physiological regulation is still unclear. Since nitric oxide (NO) participates directly in hippocampal glutamatergic signaling we investigated the neuronal role of the eIF2alpha kinase HRI, which can bind NO by a heme group, in BACE1 translation and its physiological consequences. Results: We found that BACE1 is expressed upon glutamate activation being NO the downstream effector by triggering eIF2alpha phosphorylation, as it was obtained by western blot and luciferase assay. It is due to the activation of HRI by NO as assayed by western blot and immunofluorescence with a HRI inhibitor and HRI siRNA. BACE1 expression was early detected at synaptic spines contributing to spine growth and consolidating the hippocampal memory as assayed with mice treated with HRI or neuronal NO synthase inhibitors. Innovation: We provide the first description that HRI and eIF2alpha are working in physiological conditions in brain under the control of nitric oxide and glutamate signaling, and also that BACE1 has a physiological role in hippocampal function. Conclusion: We conclude BACE1 translation is controlled by NO through HRI in glutamatergic hippocampal synapses where it plays physiological functions allowing the spine growth and memory consolidation.




19/09/2014 | Neurosci Lett   IF 2.3
Methylglyoxal reduces mitochondrial potential and activates Bax and caspase-3 in neurons: Implications for Alzheimer's disease.
Tajes M, Eraso-Pichot A, Rubio-Moscardo F, Guivernau B, Bosch-Morato M, Valls-Comamala V, Munoz FJ

Abstract:
Alzheimer's disease (AD) is characterized by the oxidative stress generated from amyloid beta-peptide (Abeta) aggregates. It produces protein nitrotyrosination, after the reaction with nitric oxide to form peroxynitrite, being triosephosphate isomerase (TPI) one of the most affected proteins. TPI is a glycolytic enzyme that catalyzes the interconversion between glyceraldehyde 3-phosphate (GAP) and dihydroxyacetone phosphate (DHAP). Methylglyoxal (MG) is a by-product of TPI activity whose production is triggered when TPI is nitrotyrosinated. MG is harmful to cells because it glycates proteins. Here we found protein glycation when human neuroblastoma cells were treated with Abeta. Moreover glycation was also observed when neuroblastoma cells overexpressed mutated TPI where Tyr165 or Tyr209, the two tyrosines close to the catalytic center, were changed by Phe in order to mimic the effect of nitrotyrosination. The pathological relevance of these findings was studied by challenging cells with Abeta oligomers and MG. A significant decrease in mitochondrial transmembrane potential, one of the first apoptotic events, was obtained. Therefore, increasing concentrations of MG were assayed searching for MG effect in neuronal apoptosis. We found a decrease of the protective Bcl2 and an increase of the proapoptotic caspase-3 and Bax levels. Our results suggest that MG is triggering apoptosis in neurons and it would play a key role in AD neurodegeneration.




08/2014 | mol membr biol   IF 2.5
The blood-brain barrier: structure, function and therapeutic approaches to cross it.
Tajes M, Ramos-Fernandez E, Weng-Jiang X, Bosch-Morato M, Guivernau B, Eraso-Pichot A, Salvador B, Fernandez-Busquets X, Roquer J, Munoz FJ

Abstract:
The blood-brain barrier (BBB) is constituted by a specialized vascular endothelium that interacts directly with astrocytes, neurons and pericytes. It protects the brain from the molecules of the systemic circulation but it has to be overcome for the proper treatment of brain cancer, psychiatric disorders or neurodegenerative diseases, which are dramatically increasing as the population ages. In the present work we have revised the current knowledge on the cellular structure of the BBB and the different procedures utilized currently and those proposed to cross it. Chemical modifications of the drugs, such as increasing their lipophilicity, turn them more prone to be internalized in the brain. Other mechanisms are the use of molecular tools to bind the drugs such as small immunoglobulins, liposomes or nanoparticles that will act as Trojan Horses favoring the drug delivery in brain. This fusion of the classical pharmacology with nanotechnology has opened a wide field to many different approaches with promising results to hypothesize that BBB will not be a major problem for the new generation of neuroactive drugs. The present review provides an overview of all state-of-the-art of the BBB structure and function, as well as of the classic strategies and these appeared in recent years to deliver drugs into the brain for the treatment of Central Nervous System (CNS) diseases.




2014 | j alzheimers dis   IF 3.9
Methylglyoxal produced by amyloid-beta peptide-induced nitrotyrosination of triosephosphate isomerase triggers neuronal death in Alzheimer's disease.
Tajes M, Eraso-Pichot A, Rubio-Moscardo F, Guivernau B, Ramos-Fernandez E, Bosch-Morato M, Guix FX, Clarimon J, Miscione GP, Boada M, Gil-Gomez G, Suzuki T, Molina H, Villa-Freixa J, Vicente R, Munoz FJ

Abstract:
Amyloid-beta peptide (Abeta) aggregates induce nitro-oxidative stress, contributing to the characteristic neurodegeneration found in Alzheimer's disease (AD). One of the most strongly nitrotyrosinated proteins in AD is the triosephosphate isomerase (TPI) enzyme which regulates glycolytic flow, and its efficiency decreased when it is nitrotyrosinated. The main aims of this study were to analyze the impact of TPI nitrotyrosination on cell viability and to identify the mechanism behind this effect. In human neuroblastoma cells (SH-SY5Y), we evaluated the effects of Abeta42 oligomers on TPI nitrotyrosination. We found an increased production of methylglyoxal (MG), a toxic byproduct of the inefficient nitro-TPI function. The proapoptotic effects of Abeta42 oligomers, such as decreasing the protective Bcl2 and increasing the proapoptotic caspase-3 and Bax, were prevented with a MG chelator. Moreover, we used a double mutant TPI (Y165F and Y209F) to mimic nitrosative modifications due to Abeta action. Neuroblastoma cells transfected with the double mutant TPI consistently triggered MG production and a decrease in cell viability due to apoptotic mechanisms. Our data show for the first time that MG is playing a key role in the neuronal death induced by Abeta oligomers. This occurs because of TPI nitrotyrosination, which affects both tyrosines associated with the catalytic center.