Angeles Rodrı́guez-Peña

University Hospital Schleswig-Holstein

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Juan Bernal

Instituto de Investigaciones Biomédicas Sols-Morreale

Alberto Múñoz

Universidad Autónoma de Madrid

Teresa Iglesias

Instituto de Salud Carlos III

Enrique Rozengurt

University of California, Los Angeles

Nieves Ibarrola

Universidad de Salamanca

Miguel A. Íñiguez

Universidad Autónoma de Madrid

Sonia Vega

Vall d'Hebron Hospital Universitari

Mónica Sobrado

Hospital Universitario de La Princesa

Margarita Díaz‐Guerra

Universidad Autónoma de Madrid

Sergio Gascón

Instituto Cajal

Cooperative Institutions

Universidad Autónoma de Madrid

Consejo Superior de Investigaciones Científicas

Instituto de Investigaciones Biomédicas Sols-Morreale

Instituto de Salud Carlos III

Centro de Investigación Biomédica en Red

Centre National de la Recherche Scientifique

Instituto Cajal

Inserm

Universidad Complutense de Madrid

Centro de Investigaciones Biológicas Margarita Salas

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Role of Thyroid Hormone on the Oligodendrocyte Type 2-Astrocyte Lineage

Springer eBooks (1998)

Ángeles Rodríguez-Peña Nieves Ibarrola Sonia Vega

10.1007/978-1-4615-5737-1_6

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Citations (0)

Kidins220/ARMS downregulation by excitotoxic activation of NMDARs reveals its involvement in neuronal survival and death pathways

Journal of Cell Science (2009)

Celia López‐Menéndez Sergio Gascón Mónica Sobrado Óscar G. Vidaurre Alonso M. Higuero

Functional and protein interactions between the N-methyl-D-aspartate type of glutamate receptor (NMDAR) and neurotrophin or ephrin receptors play essential roles in neuronal survival and differentiation. A shared downstream effector for neurotrophin- and ephrin-receptor signaling is kinase D-interacting substrate of 220 kDa (Kidins220), also known as ankyrin repeat-rich membrane spanning (ARMS). Because this molecule is obligatory for neurotrophin-induced differentiation, we investigated whether Kidins220/ARMS and NMDAR functions were related. Here, we identify an association between these proteins and discover that excitotoxicity, a specific form of neuronal death induced by NMDAR overstimulation, dramatically decreases Kidins220/ARMS levels in cortical neurons and in a model of cerebral ischemia. Kidins220/ARMS downregulation is triggered by overactivation of NMDARs containing NR2B subunits and subsequent Ca2+ influx, and involves a dual mechanism: rapid cleavage by the Ca2+-dependent protease calpain and calpain-independent silencing of Kidins220/Arms gene transcription. Additionally, Kidins220/ARMS knockdown decreases ERK activation and basal neuronal viability, and enhances neuronal death under excitotoxic conditions. Our results demonstrate Kidins220/ARMS participation in neuronal life and death pathways, and constitute the first report of its regulation under pathological conditions.

Excitotoxicity

10.1242/jcs.056473

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Citations (61)

Retinoic acid posttranscriptionally up-regulates proteolipid protein gene expression in C6 glioma cells.

Journal of Biological Chemistry (1993)

M López-Barahona M Miñano E. Mira Teresa Iglesias H.G. Stunnenberg

The proteolipid protein (PLP) gene codes for the major central nervous system myelin protein.We have studied the effects of different agents on the expression of the PLP gene in C6 glioma cells.Retinoic acid (RA), but not dexamethasone, estradiol, insulin, growth hormone, or vitamin Ds, had a drastic effect, increasing 10-20-fold the level of PLP mRNA.Concomitantly, RA also induced the appearance of the corresponding immunoreactive protein.The increase in PLP RNA level showed a slow kinetics and was blocked by cycloheximide, suggesting a posttranscriptional regulation by RA.Nuclear run-on assays confirmed that the rate of PLP gene transcription was unchanged by RA.In contrast, we found that retinoic acid augmented PLP mRNA stability, causing a substantial increase in its half-life.RA action was independent of cell density, serum, or PDGF but was partially inhibited by bFGF.On the other hand, thyroid hormone caused a moderate increase in PLP mRNA levels in C6 cells but only when the low numbers of thyroid receptors in these cells were increased by retrovirally mediated expression of an exogenous c-erbAITRa-1 gene.Our results indicate that RA specifically up-regulates PLP expression in glioma C6 cells at a posttranscriptional level by increasing PLP RNA half-life.Proteolipid protein (PLP)' is the major protein component (50% of total) of central nervous system myelin.PLP is essential for the adequate compaction of the myelin sheath which in turn is critical for normal brain function as shown by the severe consequences of PLP mutations or deficiency in rodents (jimpy, msd, md) (Hogan and Greenfield, 1984;

Proteolipid protein 1

10.1016/s0021-9258(19)74434-2

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Citations (32)

Expression of Thyroid Hormone Receptor Isoforms in the Oligodendrocyte Lineage

Neurochemical Research (2004)

Louis L. Sarliève Ángeles Rodríguez-Peña Keith Langley

Thyroid hormone receptor

Remyelination

10.1023/b:nere.0000021235.83952.9a

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Citations (38)

Expression of mitochondrial genes and of the transcription factors involved in the biogenesis of mitochondria Tfam, NRF-1 and NRF-2, in rat liver, testis and brain

Biochimie (1999)

Héctor Escrivà Ángeles Rodríguez-Peña Carmen G. Vallejo

TFAM

Transcription

10.1016/s0300-9084(99)00223-0

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Citations (29)

Optical Detection of Acoustic Cavitation through Continuous Laser in a Controlled Medium Emulating Biological Tissue

Ángeles Rodríguez-Peña A. Vera L. Leija M. I. Gutiérrez

This study proposes an optical system for the detection of cavitation in a controlled medium, emulating current acoustic detection techniques. By using a high-intensity focused ultrasound transducer and a 530 nm wavelength laser, it aims to detect the presence of microbubbles generated by cavitation. The laser interaction with the bubbles causes an alteration in the light energy, enabling its detection. The capture of the altered laser light is carried out through an optical detection system that includes a photodiode with sufficient sensitivity to detect small particles. The application of ultrasound at a power level sufficient to generate cavitation can be detected by the reflected and refracted beams when a laser is incident within the phantom in the area where bubbles are generated. Variations in intensity on the order of 1.54% and 2.88% were recorded, reflecting the presence of cavitation and offering a perspective on the advantages in terms of resolution and ease of measurement for studying the optical phenomena of cavitation and its application for health benefits.

Photodiode

Optical power

Acoustic Emission

Light intensity

10.1109/gmepe/pahce62423.2024.10534748

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Thyroid hormone regulation of RC3, a brain-specific gene encoding a protein kinase-C substrate.

Endocrinology (1993)

Miguel A. Íñiguez Ángeles Rodríguez-Peña Nieves Ibarrola Maria Aguilera Alberto Múñoz

RC3 is a brain-specific mRNA expressed in discrete neuronal groups of the forebrain that encodes a 78-amino acid protein, also called neurogranin, a calmodulin-binding, protein kinase-C substrate. Expression of RC3 mRNA was studied in normal and hypothyroid animals during the first month of life. Hypothyroid rats were produced by administration of methyl-mercapto-imidazol to the pregnant dams and subsequent surgical thyroidectomy on postnatal day 5 of the neonates. As studied by slot-blotting of total cerebrum poly(A)+ RNA, RC3 mRNA accumulates in normal brain from the fifth to seventh postnatal day, reaching maximal levels around days 10-12. RC3 mRNA accumulation in hypothyroid animals was blunted, and the maximal levels attained were about 30-50% of normal values. The effect of hypothyroidism on steady state mRNA levels was also observed by Northern blotting of RNA from cerebral cortex and striatum. As studied by immunoblotting using a polyclonal antibody, hypothyroidism also led to clear decreases in the amount of the RC3 protein in extracts from cerebral cortex, striatum, and hippocampus. A single administration of 10 micrograms T4 to hypothyroid rats on postnatal day 12 led to a steady increase in striatal RC3 mRNA from levels that were about 40% of normal to about 70% of normal at 16 h and 115% of normal at 48 h. In contrast to the effect on RC3, hypothyroidism did not affect developmental expression of the mRNA encoding GAP-43, another brain protein kinase-C substrate of axonal localization. RC3 is, thus, one of the few known neuronal genes whose expression is influenced by thyroid hormone in the brain. Thyroid hormone is required for an appropriate level of expression, not for the developmentally programmed timing of expression of the RC3 gene.

Northern blot

Neurogranin

10.1210/endo.133.2.8344193

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Citations (99)

Imbalance of neurotrophin receptor isoforms TrkB-FL/TrkB-T1 induces neuronal death in excitotoxicity

Cell Death and Disease (2012)

Óscar G. Vidaurre Sergio Gascón Rubén Deogracias Mónica Sobrado Eloy Cuadrado

A better understanding of the mechanisms underlying neuronal death in cerebral ischemia is required for the development of stroke therapies. Here we analyze the contribution of the tropomyosin-related kinase B (TrkB) neurotrophin receptor to excitotoxicity, a primary pathological mechanism in ischemia, which is induced by overstimulation of glutamate receptors of the N-methyl-D-aspartate type. We demonstrate a significant modification of TrkB expression that is strongly associated with neurodegeneration in models of ischemia and in vitro excitotoxicity. Two mechanisms cooperate for TrkB dysregulation: (1) calpain-processing of full-length TrkB (TrkB-FL), high-affinity receptor for brain-derived neurotrophic factor, which produces a truncated protein lacking the tyrosine-kinase domain and strikingly similar to the inactive TrkB-T1 isoform and (2) reverse regulation of the mRNA of these isoforms. Collectively, excitotoxicity results in a decrease of TrkB-FL, the production of truncated TrkB-FL and the upregulation of TrkB-T1. A similar neuro-specific increase of the TrkB-T1 isoform is also observed in stroke patients. A lentivirus designed for both neuro-specific TrkB-T1 interference and increased TrkB-FL expression allows recovery of the TrkB-FL/TrkB-T1 balance and protects neurons from excitotoxic death. These data implicate a combination of TrkB-FL downregulation and TrkB-T1 upregulation as significant causes of neuronal death in excitotoxicity, and reveal novel targets for the design of stroke therapies.

Excitotoxicity

Trk receptor

10.1038/cddis.2011.143

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Citations (91)

P0178 Lack of DNA methyltransferase DNMT3A in fibroblasts impairs cell growth and wound healing

Journal of Crohn s and Colitis (2025)

Celia Escudero‐Hernández Emely Hübner S Núñez-Torvisco Ángeles Rodríguez-Peña Julia Montague

Abstract Background Fibrosis in Crohn’s disease (CD) is a complication of chronic inflammatory processes that may result in impaired gastrointestinal function and bowel strictures. However, exact pathomechanisms leading to intestinal fibrosis in CD are not fully understood. Since the de novo DNA methyltransferase DNMT3A is involved in cellular differentiation processes and genetic variants have been associated with increased risk for CD, we sought to characterize how DNMT3A loss might affect fibroblasts, the key mesenchymal cells involved in fibrosis. Methods We stably deleted Dnmt3a in 3T3 fibroblast cell line using CRISPR-Cas9 technology and subsequently selected GPF-positive clones using FACS sorting. Cell cultures were performed in cell culture plates with or without 0.2% gelatin coat. Reverse transcription quantitative PCR, western blot, and immunofluorescence were used to confirm Dnmt3a gene deletion and characterize wild-type (WT) and knockout (KO) cells. Cell adhesion was evaluated by fluorescence levels of calcein acetoxymethyl ester (CAM)-labelled cells that attached to cell culture plates after 1h of culture and subsequent wash. Collagen lattice assays in presence of proinflammatory and profibrotic stimuli served to assess fibroblast contractibility. Results 3T3 fibroblasts lacking Dnmt3a acquire an activated myofibroblast phenotype (increased a-SMA expression) that also overexpress tissue remodeling matrix metalloproteinase Mmp3, and the inflammation-induced necroptosis marker RIPK3 when compared to their WT counterparts. In addition, Dnmt3a-depleted 3T3 cells adhere more strongly to cell culture plates. In presence of transforming growth factor (TGF)-b, cells embedded in a 3D collagen matrix and lacking Dnmt3a build an interconnected cellular network and contract up to a 77.78% (compared to interconnected cells that reach up to 13.73% contraction by WT cells). This contraction was independent of the presence of interleukin (IL)-11. Profibrotic factors such as bleomycin prevent intercellular network formation in both WT and KO cells; hence, incapacitating cells to contract the collagen matrix. Conclusion We conclude that Dnmt3a is crucial for fibroblast homeostasis, including cell activation and functionality. Furthermore, TGF-b induces higher fibroblast contractibility when Dnmt3a is lacking. Thus, additional characterization of Dnmt3a depletion in fibroblasts will deepen the understanding of fibrosis and may point towards new therapeutic approaches for this untreatable complication. References 1.Hampe J, Franke A, Rosenstiel P, et al. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat Genet. 2007;39(2):207-211. doi:10.1038/ng1954 2.Fazio A, Bordoni D, Kuiper JWP, et al. DNA methyltransferase 3A controls intestinal epithelial barrier function and regeneration in the colon. Nat Commun. 2022;13(1):6266. doi:10.1038/s41467-022-33844-2

DNA methyltransferase

10.1093/ecco-jcc/jjae190.0352

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Excitotoxicity and focal cerebral ischemia induce truncation of the NR2A and NR2B subunits of the NMDA receptor and cleavage of the scaffolding protein PSD-95

Molecular Psychiatry (2007)

Sergio Gascón Mónica Sobrado J.M. Roda Ángeles Rodríguez-Peña Margarita Díaz‐Guerra

Excitotoxicity

Postsynaptic density

Brain ischemia

10.1038/sj.mp.4002017

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Citations (124)