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Anton-Fernandez A.,Instituto Cajal | Anton-Fernandez A.,Technical University of Madrid | Leon-Espinosa G.,Instituto Cajal | Leon-Espinosa G.,Technical University of Madrid | And 7 more authors.
Frontiers in Neuroanatomy | Year: 2015

Hibernating animals have been used as models to study several aspects of the plastic changes that occur in the metabolism and physiology of neurons. These models are also of interest in the study of Alzheimer's disease because the microtubule-associated protein tau is hyperphosphorylated during the hibernation state known as torpor, similar to the pretangle stage of Alzheimer's disease. Hibernating animals undergo torpor periods with drops in body temperature and metabolic rate, and a virtual cessation of neural activity. These processes are accompanied by morphological and neurochemical changes in neurons, which reverse a few hours after coming out of the torpor state. Since tau has been implicated in the structural regulation of the neuronal Golgi apparatus (GA) we have used Western Blot and immunocytochemistry to analyze whether the GA is modified in cortical neurons of the Syrian hamster at different hibernation stages. The results show that, during the hibernation cycle, the GA undergo important structural changes along with differential modifications in expression levels and distribution patterns of Golgi structural proteins. These changes were accompanied by significant transitory reductions in the volume and surface area of the GA elements during torpor and arousal stages as compared with euthermic animals. © 2015 Antón-Fernández, León-Espinosa, DeFelipe and Muñoz.


Medina M.,Research Center Biomedica En Red Of Enfermedades Neurodegenerativas | Medina M.,CIEN Foundation | Avila J.,Research Center Biomedica En Red Of Enfermedades Neurodegenerativas
Expert Review of Neurotherapeutics | Year: 2014

Tau is a brain microtubule-associated protein that regulates microtubule structure and function. Prominent tau neurofibrillary pathology is a common feature in a number of neurodegenerative disorders collectively referred to as tauopathies, the most common of which is Alzheimer's disease. Beyond its classical role as a microtubule-associated protein, recent advances in our understanding of tau cellular functions have unveiled novel important tau cellular functions that may also play a pivotal role in pathogenesis and render novel targets for therapeutic intervention. Regulation of tau behavior and function under physiological and pathological conditions is mainly achieved through post-translational modifications, especially phosphorylation, which has significant implications for the development of novel therapeutic approaches in a number of neurodegenerative disorders. © Informa UK, Ltd.


Perez-Gomez E.,Complutense University of Madrid | Perez-Gomez E.,Institute Investigacion Hospital 12 Of Octubre | Andradas C.,Complutense University of Madrid | Andradas C.,Institute Investigacion Hospital 12 Of Octubre | And 42 more authors.
Journal of the National Cancer Institute | Year: 2015

Background: Pharmacological activation of cannabinoid receptors elicits antitumoral responses in different cancer models. However, the biological role of these receptors in tumor physio-pathology is still unknown. Methods: We analyzed CB2 cannabinoid receptor protein expression in two series of 166 and 483 breast tumor samples operated in the University Hospitals of Kiel, Tübingen, and Freiburg between 1997 and 2010 and CB2 mRNA expression in previously published DNA microarray datasets. The role of CB2 in oncogenesis was studied by generating a mouse line that expresses the human V-Erb-B2 Avian Erythroblastic Leukemia Viral Oncogene Homolog 2 (HER2) rat ortholog (neu) and lacks CB2 and by a variety of biochemical and cell biology approaches in human breast cancer cells in culture and in vivo, upon modulation of CB2 expression by si/shRNAs and overexpression plasmids. CB2-HER2 molecular interaction was studied by colocalization, coimmunoprecipitation, and proximity ligation assays. Statistical tests were two-sided. Results: We show an association between elevated CB2 expression in HER2+ breast tumors and poor patient prognosis (decreased overall survival, hazard ratio [HR] = 0.29, 95% confidence interval [CI] = 0.09 to 0.71, P =. 009) and higher probability to suffer local recurrence (HR = 0.09, 95% CI = 0.049 to 0.54, P =. 003) and to develop distant metastases (HR = 0.33, 95% CI = 0.13 to 0.75, P =. 009). We also demonstrate that genetic inactivation of CB2 impairs tumor generation and progression in MMTV-neu mice. Moreover, we show that HER2 upregulates CB2 expression by activating the transcription factor ELK1 via the ERK cascade and that an increased CB2 expression activates the HER2 pro-oncogenic signaling at the level of the tyrosine kinase c-SRC. Finally, we show HER2 and CB2 form heteromers in cancer cells. Conclusions: Our findings reveal an unprecedented role of CB2 as a pivotal regulator of HER2 pro-oncogenic signaling in breast cancer, and they suggest that CB2 may be a biomarker with prognostic value in these tumors. © 2015 The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.


Sanchez-Mut J.V.,Bellvitge Biomedical Research Institute | Heyn H.,Bellvitge Biomedical Research Institute | Vidal E.,Bellvitge Biomedical Research Institute | Moran S.,Bellvitge Biomedical Research Institute | And 22 more authors.
Translational Psychiatry | Year: 2016

Different neurodegenerative disorders often show similar lesions, such as the presence of amyloid plaques, TAU-neurotangles and synuclein inclusions. The genetically inherited forms are rare, so we wondered whether shared epigenetic aberrations, such as those affecting DNA methylation, might also exist. The studied samples were gray matter samples from the prefrontal cortex of control and neurodegenerative disease-associated cases. We performed the DNA methylation analyses of Alzheimer's disease, dementia with Lewy bodies, Parkinson's disease and Alzheimer-like neurodegenerative profile associated with Down's syndrome samples. The DNA methylation landscapes obtained show that neurodegenerative diseases share similar aberrant CpG methylation shifts targeting a defined gene set. Our findings suggest that neurodegenerative disorders might have similar pathogenetic mechanisms that subsequently evolve into different clinical entities. The identified aberrant DNA methylation changes can be used as biomarkers of the disorders and as potential new targets for the development of new therapies.


Sivera R.,Hospital Univesitari i Politecnic la Fe | Sevilla T.,Hospital Univesitari i Politecnic la Fe | Sevilla T.,Research Center Biomedica En Red Of Enfermedades Neurodegenerativas | Sevilla T.,University of Valencia | And 20 more authors.
Neurology | Year: 2013

Objectives: To determine the genetic distribution and the phenotypic correlation of an extensive series of patients with Charcot-Marie-Tooth disease in a geographically well-defined Mediterranean area. Methods: A thorough genetic screening, including most of the known genes involved in this disease, was performed and analyzed in this longitudinal descriptive study. Clinical data were analyzed and compared among the genetic subgroups. Results: Molecular diagnosis was accomplished in 365 of 438 patients (83.3%), with a higher success rate in demyelinating forms of the disease. The CMT1A duplication (PMP22 gene) was the most frequent genetic diagnosis (50.4%), followed by mutations in the GJB1 gene (15.3%), and in the GDAP1 gene (11.5%). Mutations in 13 other genes were identified, but were much less frequent. Sixteen novel mutations were detected and characterized phenotypically. Conclusions: The relatively high frequency of GDAP1 mutations, coupled with the scarceness of MFN2 mutations (1.1%) and the high proportion of recessive inheritance (11.6%) in this series exemplify the particularity of the genetic distribution of Charcot-Marie-Tooth disease in this region. © 2013 American Academy of Neurology.


Lopez-Gonzalez I.,Bellvitge Hospital Universitari Of Bellvitge | Schluter A.,Hospitalet Of Llobregat | Schluter A.,Center for Biomedical Research on Rare Diseases | Aso E.,Bellvitge Hospital Universitari Of Bellvitge | And 16 more authors.
Journal of Neuropathology and Experimental Neurology | Year: 2015

To understand neuroinflammation-related gene regulation during normal aging and in sporadic Alzheimer disease (sAD), we performed functional genomics analysis and analyzed messenger RNA (mRNA) expression by quantitative reverse transcriptionYpolymerase chain reaction of 22 genes involved in neuroinflammation-like responses in the cerebral cortex of wild-type and APP/PS1 transgenic mice. For direct comparisons, mRNA expression of 18 of the same genes was then analyzed in the entorhinal cortex, orbitofrontal cortex, and frontal cortex area 8 of middle-aged human subjects lacking Alzheimer diseaseYrelated pathology and in older subjects with sAD pathology covering Stages IYII/0(A), IIIYIV/AYB, and VYVI/C of Braak and Braak classification. Modifications of cytokine and immune mediator mRNA expression were found with normal aging in wild-type mice and in middle-aged individuals and patients with early stages of sAD-related pathology; these were accompanied by increased protein expression of certain mediators in ramified microglia. In APP/PS1 mice, inflammatory changes coincided with β-amyloid (Aβ) deposition; increased levels of soluble oligomers paralleled the modified mRNA expression of cytokines and mediators in wild-type mice. In patients with sAD, regulation was stage- and region-dependent and not merely acceleration and exacerbation of mRNA regulation with aging. Gene regulation at first stages of AD was not related to hyperphosphorylated tau deposition in neurofibrillary tangles, Aβ plaque burden, concentration of Aβ1-40 (Aβ40) and Aβ1-42 (Aβ42), or fibrillar Aβ linked to membranes but rather to increased levels of soluble oligomers. Thus, species differences and regionand stage-dependent inflammatory responses in sAD, particularly at the initial stages, indicate the need to identify new anti-inflammatory compounds with specific molecular therapeutic targets. © 2015 by the American Association of Neuropathologists, Inc.


Ardite E.,University Pompeu Fabra | Ardite E.,Research Center Biomedica En Red Of Enfermedades Neurodegenerativas | Perdiguero E.,University Pompeu Fabra | Perdiguero E.,Research Center Biomedica En Red Of Enfermedades Neurodegenerativas | And 9 more authors.
Journal of Cell Biology | Year: 2012

Disruption of skeletal muscle homeostasis by substitution with fibrotic tissue constitutes the principal cause of death in Duchenne muscular dystrophy (DMD) patients, yet the implicated fibrogenic mechanisms remain poorly understood. This study identifies the extracellular PAI-1/urokinase-type plasminogen activator (uPA) balance as an important regulator of microribonucleic acid (miR)-21 biogenesis, controlling age-associated muscle fibrosis and dystrophy progression. Genetic loss of PAI-1 in mdx dystrophic mice anticipated muscle fibrosis through these sequential mechanisms: the alteration of collagen metabolism by uPA-mediated proteolytic processing of transforming growth factor (TGF)-β in muscle fibroblasts and the activation of miR-21 expression, which inhibited phosphatase and tensin homologue and enhanced AKT signaling, thus endowing TGF-β with a remarkable cell proliferation-promoting potential. Ageassociated fibrogenesis and muscle deterioration in mdx mice, as well as exacerbated dystrophy in young PAI-1 -/-mdx mice, could be reversed by miR-21 or uPA-selective interference, whereas forced miR-21 overexpression aggravated disease severity. The PAI-1-miR-21 fibrogenic axis also appeared dysregulated in muscle of DMD patients, providing a basis for effectively targeting fibrosis and muscular dystrophies in currently untreatable individuals. © 2012 Ardite et al.


Gil V.,Cellular Bioengineering | Gil V.,University of Barcelona | Gil V.,Research Center Biomedica En Red Of Enfermedades Neurodegenerativas | Nocentini S.,Cellular Bioengineering | And 5 more authors.
Frontiers in Neuroanatomy | Year: 2014

Santiago Ramón y Cajal developed a great body of scientific research during the last decade of 19th century, mainly between 1888 and 1892, when he published more than 30 manuscripts. The neuronal theory, the structure of dendrites and spines, and fine microscopic descriptions of numerous neural circuits are among these studies. In addition, numerous cell types (neuronal and glial) were described by Ramón y Cajal during this time using this "reazione nera" or Golgi method. Among these neurons were the special cells of the molecular layer of the neocortex. These cells were also termed Cajal cells or Retzius cells by other colleagues. Today these cells are known as Cajal-Retzius cells. From the earliest description, several biological aspects of these fascinating cells have been analyzed (e.g., cell morphology, physiological properties, origin and cellular fate, putative function during cortical development, etc). In this review we will summarize in a temporal basis the emerging knowledge concerning this cell population with specific attention the pioneer studies of Santiago Ramón y Cajal. © 2014 Gil, Nocentini and del Río.


Fernandez-Santiago R.,University of Barcelona | Fernandez-Santiago R.,Research Center Biomedica En Red Of Enfermedades Neurodegenerativas | Iranzo A.,University of Barcelona | Iranzo A.,Research Center Biomedica En Red Of Enfermedades Neurodegenerativas | And 12 more authors.
Neurology | Year: 2016

Most patients with idiopathic REM sleep behavior disorder (IRBD) are diagnosed with the synucleinopathies Parkinson disease (PD) and dementia with Lewy bodies. Conversion rates have been estimated to be 35% at 5 years, 73% at 10 years, and 92% at 14 years after IRBD diagnosis. 1 Accordingly, IRBD is considered as a marker of the prodromal stage of synucleinopathies. In PD, RBD occurs in about 50% of the patients and in 18% of them, RBD symptoms precede the onset of parkinsonism. 2 Most cases of PD are sporadic, but approximately 5% to 10% of cases encompass monogenic forms caused by mutations in PD-associated genes. Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene represent the most common genetic cause of both familial PD and sporadic PD (sPD). Indeed, the G2019S mutation has been detected in up to 6% of familial and 3% of sPD cases in Europeans. 3 Moreover, the LRRK2-associated PD form (LRRK2-PD) is clinical and neuropathologically similar to sPD lacking LRRK2 mutations. © 2016 American Academy of Neurology.


Ansoleaga B.,Bellvitge University Hospital | Garcia-Esparcia P.,Bellvitge University Hospital | Llorens F.,Bellvitge University Hospital | Llorens F.,Research Center Biomedica En Red Of Enfermedades Neurodegenerativas | And 5 more authors.
Neuroscience | Year: 2013

Recently, we have shown the expression of novel chemoreceptors corresponding to the olfactory receptor (OR) and taste receptor (TASR) families in the human brain. We have also shown dysregulation of ORs and TASRs in the cerebral cortex in Parkinson's disease. The present study demonstrates the presence of OR mRNA and mRNA of obligated downstream components of OR signaling adenylyl cyclase 3 (ADYLC3) and olfactory G protein (Gnal) in the cerebral cortex of the mouse. Dysregulation of selected ORs and TASRs has been found in the entorhinal cortex and frontal cortex in Alzheimer's disease (AD) in a gradient compatible with Braak and Braak staging; frontal cortex in terminal stages of Progressive Supranuclear Palsy; and frontal cortex and cerebellum in Creutzfeldt-Jakob disease subtypes methionine/methionine at codón 129 of PRNP (MM1) and valine/valine at codón 129 of PRNP (VV2). Altered OR, ADYLC3 and Gnal mRNA expression with disease progression has also been found in APP/PS1 transgenic mice, used as a model of AD. The function of these orphan receptors is not known, but probably related to cell signaling pathways responding to unidentified ligands.Variability in the drift, either down- or up-regulation, of dysregulated genes, suggests that central ORs and TASRs are vulnerable to variegated neurodegenerative diseases with cortical involvement, and that altered expression of ORs and TASRs is not a mere reflection of neuronal loss but rather a modulated pathological response. © 2013 IBRO.

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