Péptidos y anticuerpos útiles para la elaboración de medicamentos para el tratamiento o prevención de enfermedades humanas neurodegenerativas, medicamentos así obtenidos y sus aplicaciones

Péptidos y anticuerpos útiles para la elaboración de medicamentos para el tratamiento o prevención de enfermedades humanas neurodegenerativas, medicamentos así obtenidos y sus aplicaciones. La presente invención describe inhibidores de la expresión génica del gen que codifica para la proteína NP1, que actúa como un inductor de apoptosis neural y neurodegeneración, útiles para la elaboración de medicamentos o composiciones farmacéuticas para el tratamiento o prevención de enfermedades humanas neurológicas, preferentemente enfermedades neurodegenerativas. Más preferentemente, la enfermedad neurodegenerativa es el Alzheimer. Estos inhibidores incluyen anticuerpos específicos de la proteína NP1 humana así como de péptidos derivados de la misma que pueden ser utilizados en procedimientos de inmunización pasiva y activa, respectivamente, frente a estas enfermedades.Peer reviewedConsejo Superior de Investigaciones Científicas (España)A1 Solicitud de patente con informe sobre el estado de la técnic

The Armc10/SVH gene: Genome context, regulation of mitochondrial dynamics and protection against Aß-induced mitochondrial fragmentation

Mitochondrial function and dynamics are essential for neurotransmission, neural function and neuronal viability. Recently, we showed that the eutherian-specific Armcx gene cluster (Armcx1-6 genes), located in the X chromosome, encodes for a new family of proteins that localise to mitochondria, regulating mitochondrial trafficking. The Armcx gene cluster evolved by retrotransposition of the Armc10 gene mRNA, which is present in all vertebrates and is considered to be the ancestor gene. Here we investigate the genomic organisation, mitochondrial functions and putative neuroprotective role of the Armc10 ancestor gene. The genomic context of the Armc10 locus shows considerable syntenic conservation among vertebrates, and sequence comparisons and CHIP-data suggest the presence of at least three conserved enhancers. We also show that the Armc10 protein localises to mitochondria and that it is highly expressed in the brain. Furthermore, we show that Armc10 levels regulate mitochondrial trafficking in neurons, but not mitochondrial aggregation, by controlling the number of moving mitochondria. We further demonstrate that the Armc10 protein interacts with the KIF5/Miro1-2/Trak2 trafficking complex. Finally, we show that overexpression of Armc10 in neurons prevents Aß-induced mitochondrial fission and neuronal death. Our data suggest both conserved and differential roles of the Armc10/Armcx gene family in regulating mitochondrial dynamics in neurons, and underscore a protective effect of the Armc10 gene against Aß-induced toxicity. Overall, our findings support a further degree of regulation of mitochondrial dynamics in the brain of more evolved mammals. © 2014 Macmillan Publishers Limited All rights reserved.This project was supported by grants BFU2008-3980 and SAF2011-13232-E (Acciones Complementarias) (MINECO, Spain) to ES, by grant BFU2010-21507 to FU, by grant SAF2011-23550 to RT, by grant ‘BFU2011-23921’ and the ICREA Academia Prize (Generalitat de Catalunya) to JGF, and by a grant from the CIBERNED. SM and EN hold FPI fellowshipsPeer Reviewe

The Eutherian Armcx genes regulate mitochondrial trafficking in neurons and interact with Miro and Trak2

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivative Works 3.0 Unported License.-- et al.Brain function requires neuronal activity-dependent energy consumption. Neuronal energy supply is controlled by molecular mechanisms that regulate mitochondrial dynamics, including Kinesin motors and Mitofusins, Miro1-2 and Trak2 proteins. Here we show a new protein family that localizes to the mitochondria and controls mitochondrial dynamics. This family of proteins is encoded by an array of armadillo (Arm) repeat-containing genes located on the X chromosome. The Armcx cluster is unique to Eutherian mammals and evolved from a single ancestor gene (Armc10). We show that these genes are highly expressed in the developing and adult nervous system. Furthermore, we demonstrate that Armcx3 expression levels regulate mitochondrial dynamics and trafficking in neurons, and that Alex3 interacts with the Kinesin/Miro/Trak2 complex in a Ca 2+ -dependent manner. Our data provide evidence of a new Eutherian-specific family of mitochondrial proteins that controls mitochondrial dynamics and indicate that this key process is differentially regulated in the brain of higher vertebrates. © 2012 Macmillan Publishers Limited. All rights reserved.This project was supported by grant BFU2008-3980 (Ministerio de Ciencia e Innovación (MICINN), Spain) and grants from the 'Marató de TV3' and 'Caixa Catalunya-Obra Social' Foundations to E. S., by grant BFU2011-23921 (MICINN) and the ICREA Academia Prize (Generalitat de Catalunya) to J.G.-F., by grants PI07/0715 (Fondo de Investigación Sanitaria) to F. B., by grant SAF2008-03514 to R. T. and by grants from the EU-ERA-Net program and MICINN (SAF2008-03175-E, BFU2010-17379 and Red de Terapia Celular, RD06/0010/0000) to J.G.-S. I. S. holds an IEF Postdoctoral fellowship funded by the Marie Curie FP7 'People' Programme.Peer Reviewe

Associative learning and CA3–CA1 synaptic plasticity are impaired in D1r Null, Drd1a–/– mice and in hippocampal siRNA silenced Drd1a mice

Associative learning depends on multiple cortical and subcortical structures, including striatum, hippocampus, and amygdala. Both glutamatergic and dopaminergic neurotransmitter systems have been implicated in learning and memory consolidation. While the role of glutamate is well established, the role of dopamine and its receptors in these processes is less clear. In this study, we used two models of dopamine D₁ receptor (D₁R, Drd1a) loss, D₁R knock-out mice (Drd1a–/–) and mice with intrahippocampal injections of Drd1a-siRNA (small interfering RNA), to study the role of D₁R in different models of learning, hippocampal long-term potentiation (LTP) and associated gene expression. D₁R loss markedly reduced spatial learning, fear learning, and classical conditioning of the eyelid response, as well as the associated activity-dependent synaptic plasticity in the hippocampal CA1–CA3 synapse. These results provide the first experimental demonstration that D₁R is required for trace eyeblink conditioning and associated changes in synaptic strength in hippocampus of behaving mice. Drd1a-siRNA mice were indistinguishable from Drd1a–/– mice in all experiments, indicating that hippocampal knockdown was as effective as global inactivation and that the observed effects are caused by loss of D₁R and not by indirect developmental effects of Drd1a–/–. Finally, in vivo LTP and LTP-induced expression of Egr1 in the hippocampus were significantly reduced in Drd1a–/– and Drd1a-siRNA, indicating an important role for D₁R in these processes. Our data reveal a functional relationship between acquisition of associative learning, increase in synaptic strength at the CA3–CA1 synapse, and Egr1 induction in the hippocampus by demonstrating that all three are dramatically impaired when D₁R is eliminated or reduced

Uridine 5′-triphosphate promotes in vitro Schwannoma cell migration through matrix metalloproteinase-2 activation

In response to peripheral nerve injury, Schwann cells adopt a migratory phenotype and modify the extracellular matrix to make it permissive for cell migration and axonal re-growth. Uridine 5′-triphosphate (UTP) and other nucleotides are released during nerve injury and activate purinergic receptors expressed on the Schwann cell surface, but little is known about the involvement of purine signalling in wound healing. We studied the effect of UTP on Schwannoma cell migration and wound closure and the intracellular signaling pathways involved. We found that UTP treatment induced Schwannoma cell migration through activation of P2Y2 receptors and through the increase of extracellular matrix metalloproteinase-2 (MMP-2) activation and expression. Knockdown P2Y2 receptor or MMP-2 expression greatly reduced wound closure and MMP-2 activation induced by UTP. MMP-2 activation evoked by injury or UTP was also mediated by phosphorylation of all 3 major mitogen-activated protein kinases (MAPKs): JNK, ERK1/2, and p38. Inhibition of these MAPK pathways decreased both MMP-2 activation and cell migration. Interestingly, MAPK phosphorylation evoked by UTP exhibited a biphasic pattern, with an early transient phosphorylation 5 min after treatment, and a late and sustained phosphorylation that appeared at 6 h and lasted up to 24 h. Inhibition of MMP-2 activity selectively blocked the late, but not the transient, phase of MAPK activation. These results suggest that MMP-2 activation and late MAPK phosphorylation are part of a positive feedback mechanism to maintain the migratory phenotype for wound healing. In conclusion, our findings show that treatment with UTP stimulates in vitro Schwannoma cell migration and wound repair through a MMP-2-dependent mechanism via P2Y2 receptors and MAPK pathway activation. © 2014 Lamarca et al.This research was supported by an unrestricted research grant from Ferrer S.A. (Barcelona, Spain) and by grant SAF2011-23550 from Ministerio de Economia y Competitividad of SpainPeer Reviewe

Cell-Free DNA as a Prognostic Biomarker for Monitoring Muscle-Invasive Bladder Cancer

Cell-free DNA (cfDNA) has recently emerged as a real-time biomarker for diagnosis, monitoring and prediction of therapy response in tumoral disease. Here, we evaluated cfDNA as a prognostic biomarker for monitoring muscle-invasive bladder cancer (MIBC) patients at different follow-up time points. Blood samples from 37 MIBC patients who underwent radical cystectomy (RC) were collected at cystectomy and 1, 4, 12 and 24 months later. Plasma cfDNA amount and fragmentation patterns were determined. Four mutations were analyzed in cfDNA to detect circulating tumor DNA (ctDNA) during patient follow-up. During a median follow-up of 36 months, 46% of patients progressed; median time to progression was 10 months. cfDNA levels and ctDNA status four months after RC were identified as independent prognostic biomarkers of tumor progression (HR 5.290; p = 0.033) and cancer-specific survival (HR 4.199; p = 0.038), respectively. Furthermore, ctDNA clearance four months after RC was significantly associated with patients’ clinical outcomes. In conclusion, cfDNA levels and ctDNA status four months after RC have prognostic implications in MIBC patients. In addition, cfDNA monitoring is useful to predict patient outcomes after RC. cfDNA analysis in the clinical setting could greatly improve MIBC patient management.This research was funded by the Instituto de Salud Carlos III (ISCIII) through the Plan Estatal de Investigación Científica y Técnica y de Innovación 2018–2020, project reference number PI17/01343, and co-funded by the European Regional Development Fund (ERDF)

The Eutherian Armcx genes regulate mitochondrial trafficking in neurons and interact with Miro and Trak2

Producción CientíficaBrain function requires neuronal activity-dependent energy consumption. Neuronal energy supply is controlled by molecular mechanisms that regulate mitochondrial dynamics, including Kinesin motors and Mitofusins, Miro1-2 and Trak2 proteins. Here we show a new protein family that localizes to the mitochondria and controls mitochondrial dynamics. This family of proteins is encoded by an array of armadillo (Arm) repeat-containing genes located on the X chromosome. The Armcx cluster is unique to Eutherian mammals and evolved from a single ancestor gene (Armc10). We show that these genes are highly expressed in the developing and adult nervous system. Furthermore, we demonstrate that Armcx3 expression levels regulate mitochondrial dynamics and trafficking in neurons, and that Alex3 interacts with the Kinesin/Miro/Trak2 complex in a Ca2 + -dependent manner. Our data provide evidence of a new Eutherian-specific family of mitochondrial proteins that controls mitochondrial dynamics and indicate that this key process is differentially regulated in the brain of higher vertebrates.2015-03-3

Molecular Basis for Maternal Inheritance of Human Mitochondrial DNA

Uniparental inheritance of mitochondrial DNA (mtDNA) is an evolutionary trait found in nearly all eukaryotes. In many species, including humans, the sperm mitochondria are introduced to the oocyte during fertilization1, 2. The mechanisms hypothesized to prevent paternal mtDNA transmission include ubiquitination of the sperm mitochondria and mitophagy3, 4. However, whether these mechanisms play a decisive role in paternal mtDNA elimination has been disputed5, 6. We found that mitochondria in human spermatozoa are devoid of mtDNA and lack mitochondrial transcription factor A (TFAM), the major nucleoid protein required to protect, maintain, and transcribe mtDNA. During spermatogenesis, sperm cells express an isoform of TFAM, which retains the mitochondrial pre-sequence, ordinarily removed upon mitochondrial import. Phosphorylation of this pre-sequence prevents mitochondrial import and directs TFAM to the spermatozoon nucleus. TFAM re-localization from the mitochondria of spermatogonia to the spermatozoa nucleus directly correlates with the elimination of mitochondrial DNA, thereby explaining maternal inheritance in this species.National Institutes of Health grant R35 GM131832 (DT). PID2020-115091RB-I00, MCIN/AEI/10.13039/501100011033 Spain (RT). PI2020/09-4, CIBERNED, Instituto de Salud Carlos III (ISCIII) Spain (RT).N

Neuronal Pentraxin 1 negatively regulates excitatory synapse number

Trabajo presentado en la 43rd Annual Winter Conference on Brain Research, celebrada en Breckenridge, Colorado, Estados Unidos, del 23 al 29 de enero de 2010Peer Reviewe

The mitocondrial DNA hypothesis of Alzheimer's disease: research on molecular mechanisms of neurodegeneration

Trabajo presentado en la 1st Neurobiology Meeting, celebrado en Puebla, Pue., México, del 2 al 6 de abril de 2016Peer Reviewe