Center for Molecular Biology Severo Ochoa UAM
Center for Molecular Biology Severo Ochoa UAM
Ettcheto M.,University of Barcelona |
Ettcheto M.,CIBER ISCIII |
Junyent F.,University of Barcelona |
Junyent F.,CIBER ISCIII |
And 17 more authors.
Molecular Neurobiology | Year: 2015
The Fas receptor (FasR)/Fas ligand (FasL) system plays a significant role in the process of neuronal loss in neurological disorders. Thus, in the present study, we used a real-time PCR array focused apoptosis (Mouse Apoptosis RT2 PCR Array) to study the role of the Fas pathway in the apoptotic process that occurs in a kainic acid (KA) mice experimental model. In fact, significant changes in the transcriptional activity of a total of 23 genes were found in the hippocampus of wild-type C57BL/6 mice after 12 h of KA treatment compared to untreated mice. Among the up-regulated genes, we found key factors involved in the extrinsic apoptotic pathway, such as tnf, fas and fasL, and also in caspase genes (caspase-4, caspase-8 and caspase-3). To discern the importance of the FasR/FasL pathway, mice lacking the functional Fas death receptor (lpr) were also treated with KA. After 24 h of neurotoxin treatment, lpr mice exhibited a reduced number of apoptotic positive cells, determined by the terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) method in different regions of the hippocampus, when compared to wild-type mice. In addition, treatment of lpr mice with KA did not produce significant changes in the transcriptional activity of genes related to apoptosis in the hippocampus, either in the fas and fas ligand genes or in caspase-4 and caspase-8 and the executioner caspase-3 genes, as occurred in wild-type C57BL/6 mice. Thus, these data provide direct evidence that Fas signalling plays a key role in the induction of apoptosis in the hippocampus following KA treatment, making the inhibition of the death receptor pathway a potentially suitable target for excitotoxicity neuroprotection in neurological conditions such as epilepsy. © 2014, Springer Science+Business Media New York.
Fernandez-Nogales M.,Center for Molecular Biology Severo Ochoa UAM |
Fernandez-Nogales M.,CIBER ISCIII |
Hernandez F.,Center for Molecular Biology Severo Ochoa UAM |
Hernandez F.,CIBER ISCIII |
And 14 more authors.
Human Molecular Genetics | Year: 2015
Huntington's disease (HD) is a hereditary neurodegenerative disorder characterized by brain atrophy particularly in striatum leading to personality changes, chorea and dementia. Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase in the crossroad of many signaling pathways that is highly pleiotropic as it phosphorylates more than hundred substrates including structural, metabolic, and signaling proteins. Increased GSK-3 activity is believed to contribute to the pathogenesis of neurodegenerative diseases like Alzheimer's disease and GSK-3 inhibitors have been postulated as therapeutic agents for neurodegeneration. Regarding HD, GSK-3 inhibitors have shown beneficial effects in cell and invertebrate animal models but no evident efficacy in mouse models. Intriguingly, those studies were performed without interrogating GSK-3 level and activity in HD brain. Herewe aim to explore the level and also the enzymatic activity of GSK-3 in the striatum and other less affected brain regions of HD patients and of the R6/1 mouse model to then elucidate the possible contribution of its alteration to HD pathogenesis by genetic manipulation in mice.We report a dramatic decrease in GSK-3 levels and activity in striatum and cortex of HD patients with similar results in the mouse model. Correction of the GSK-3 deficit inHDmice, by combining with transgenic mice with conditional GSK-3 expression, resulted in amelioration of their brain atrophy and behavioral motor and learning deficits. Thus, our results demonstrate that decreased brain GSK-3 contributes to HD neurological phenotype and open new therapeutic opportunities based on increasing GSK-3 activity or attenuating the harmful consequences of its decrease. © The Author 2015.
Hernandez-Ortega K.,University of Barcelona |
Hernandez-Ortega K.,CIBER ISCIII |
Garcia-Esparcia P.,University of Barcelona |
Garcia-Esparcia P.,CIBER ISCIII |
And 5 more authors.
Brain Pathology | Year: 2016
Ribosomes and protein synthesis have been reported to be altered in the cerebral cortex at advanced stages of Alzheimer's disease (AD). Modifications in the hippocampus with disease progression have not been assessed. Sixty-seven cases including middle-aged (MA) and AD stages I–VI were analyzed. Nucleolar chaperones nucleolin, nucleophosmin and nucleoplasmin 3, and upstream binding transcription factor RNA polymerase I gene (UBTF) mRNAs are abnormally regulated and their protein levels reduced in AD. Histone modifications dimethylated histone H3K9 (H3K9me2) and acetylated histone H3K12 (H3K12ac) are decreased in CA1. Nuclear tau declines in CA1 and dentate gyrus (DG), and practically disappears in neurons with neurofibrillary tangles. Subunit 28 ribosomal RNA (28S rRNA) expression is altered in CA1 and DG in AD. Several genes encoding ribosomal proteins are abnormally regulated and protein levels of translation initiation factors eIF2α, eIF3η and eIF5, and elongation factor eEF2, are altered in the CA1 region in AD. These findings show alterations in the protein synthesis machinery in AD involving the nucleolus, nucleus and ribosomes in the hippocampus in AD some of them starting at first stages (I–II) preceding neuron loss. These changes may lie behind reduced numbers of dendritic branches and reduced synapses of CA1 and DG neurons which cause hippocampal atrophy. © 2015 International Society of Neuropathology