60f Ginés Padrós, Silvia [WorldCat Identities]
WorldCat Identities

Ginés Padrós, Silvia

Overview
Works: 14 works in 19 publications in 2 languages and 24 library holdings
Roles: Other, Author, Contributor
Publication Timeline
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Most widely held works by Silvia Ginés Padrós
Multifuncionalidad de la adenosina desaminasa de la superficie celular y de sus proteínas de unión by Silvia Ginés Padrós( Book )

3 editions published between 2000 and 2009 in Spanish and held by 3 WorldCat member libraries worldwide

Cdk5 Contributes to Huntington's Disease Learning and Memory Deficits via Modulation of Brain Region-Specific Substrates by Elena Alvarez-Periel( )

1 edition published in 2017 in English and held by 2 WorldCat member libraries worldwide

Estudio de las vías de supervivencia y muerte neuronal en modelos de la enfermedad de Huntington by Paola Paoletti Rubia( Book )

2 editions published between 2010 and 2011 in Spanish and held by 2 WorldCat member libraries worldwide

Polyglutamine expansion affects huntingtin conformation in multiple Huntington's disease models by Manuel Daldin( )

1 edition published in 2017 in English and held by 2 WorldCat member libraries worldwide

BDNF Induces Striatal-Enriched Protein Tyrosine Phosphatase 61 Degradation Through the Proteasome by Ana Saavedra( )

1 edition published in 2015 in English and held by 2 WorldCat member libraries worldwide

Description and validation of new therapeutical targets to prevent neurodegenertlion and cognitive deficits in Huntington's disease by Maria del Mar Puigdellívol Cañadell( Book )

2 editions published between 2014 and 2015 in English and held by 2 WorldCat member libraries worldwide

La malaltia de Huntington (MH) és un desordre neurodegeneratiu caracteritzat per la disfunció i mort neuronal de regions específiques del cervell. La regió més afectada és l'estriat (nuclis caudat i putamen en humans), tot i que en estadis més avançats de la malaltia s'ha descrit una atròfia i pèrdua neuronal del còrtex cerebral i hipocamp (Vonsattel et al., 1985;Vonsattel and DiFiglia, 1998). La temprana disfuncionalitat de les neurones hipocampals i corticals es creu crítica per restablir les deficiències cognitives i de memòria en aquesta patologia. La malaltia s'hereta de forma autosòmica dominant i és causada per la mutació del gen IT15, localitzat en el braç curt del cromosoma 4 (4p.16.3), que codifica per la proteïna anomenada huntingtina (htt). Aquesta mutació va ser identificada l'any 1993 com una expansió de repeticions del triplet CAG que codifiquen per una regió poliglutamínica (poliQ) a l'extrem N-terminal de la proteïna htt (350KDa) (HDCRG, 1993). En individus sans, el nombre de repeticions oscil·la de 6 a 35; quan el nombre de repeticions d'aquest triplet és superior a 40, l'individu desenvoluparà la malaltia. Les primeres manifestacions de la malaltia solen produir-se als 35 anys d'edat conduint a la mort 15-­20 anys després de l'aparició dels símptomes (Bates, 2003;Martin and Gusella, 1986). La simptomatologia inclou disfunció motora, associada majoritàriament a l'atròfia estriatal, acompanyada de trastorns cognitius i emocionals associats a l'afectació corticoestriatal i hipocampal que son de manifestació primerenca, fins i tot prèvia a la simptomatologia motora. Aquestes alteracions cognitives i emocionals constitueixen un dels pilars discapacitants en aquesta patologia, per això al llarg d'aquesta Tesi doctoral proposem un estudi dual que ens permeti definir diverses estratègies terapèutiques dirigides al tractament d'ambdues simptomatologies: motora i cognitiva. Si bé es coneix que aquesta mutació és la causant de la malaltia, avui en dia no es coneixen els mecanismes cel·lulars i moleculars responsables de la disfunció i mort neuronal en la MH. Diversos estudis han postulat que la pèrdua de funció de la proteïna wild-type i/o el guany de funció de la proteïna mutada (mhtt) juguen un paper clau en el desenvolupament de la malaltia. Així s'ha descrit que l'expressió de la proteïna huntingtina mutada resulta en l'alteració de diversos processos cel·lulars i moleculars, tals com l'agregació proteica, alteracions en el sistema ubiqüitina­proteosoma, desregulació en la maquinària transcripcional així com en la remodelació de la cromatina, alteracions en la síntesi proteica, reducció del suport tròfic, alteracions en les vies de senyalització intracel·lulars, alteració en la homeòstasis del calci, dany mitocondrial, excitotoxicitat, activació de caspases, alteracions en les interaccions proteïna-proteïna i alteració en la circuiteria neuronal (Cattaneo et al., 2005;Zuccato and Cattaneo, 2009). En aquesta Tesis ens hem centrat en estudiar alguns dels mecanismes moleculars implicats en la mort neuronal, així com en els dèficits cognitius i alteracions en la plasticitat sinàptica produïda per la presència de la huntingtina mutada, mitjançant l'estudi de les alteracions produïdes en: 1) maquinària transcripcional, 2) suport neurotròfic, 3) canvis estructurals en les sinapsis excitadores, 4) senyalització de proteïnes cinasa i fosfatasa i 5) formació d'heteròmers entre receptors acoblats a proteïnes G
Early Downregulation of p75NTR by Genetic and Pharmacological Approaches Delays the Onset of Motor Deficits and Striatal Dysfunction in Huntington's Disease Mice by Nuria Suelves( )

1 edition published in 2018 in English and held by 2 WorldCat member libraries worldwide

Early Environmental Enrichment Enhances Abnormal Brain Connectivity in a Rabbit Model of Intrauterine Growth Restriction by Miriam Illa( )

1 edition published in 2017 in English and held by 2 WorldCat member libraries worldwide

Reversal of a full-length mutant huntingtin neuronal cell phenotype by chemical inhibitors of polyglutamine-mediated aggregation by Jin Wang( )

1 edition published in 2005 in English and held by 2 WorldCat member libraries worldwide

Study of mitochondrial dysfunction mechanisms in Huntington's disease striatal degeneration by Marta Cherubini( Book )

2 editions published between 2016 and 2017 in English and held by 2 WorldCat member libraries worldwide

Huntington's disease (HD) is an autosomal-dominant inherited neurodegenerative disorder, characterized by progressive behavioral, motor and cognitive deficits (HDCRG, 1993; Ross & Margolis, 2001). The predominant neuropathological hallmark of HD is the selective loss of medium spiny neurons within the striatum that extends to other brain regions with the progression of the disease (Martin & Gusella, 1986). Although mutant huntingtin (mHtt) represents a key factor in the pathogenesis of the disease, the molecular mechanisms underlying the preferential vulnerability of the striatum to mHtt toxicity remain unclear. Compelling evidence suggest that mitochondrial defects may play a crucial role in the disease, however, it is still debated whether mitochondrial dysfunction represents just an epiphenomenon of the cellular degeneration or it has an actual pathogenic role. In this Thesis, the general purpose was to identify possible mitochondrial impaired mechanisms and to investigate their role in the selective striatal vulnerability of HD, in order to provide important insights for the development of new therapeutic strategies. The first aim was to clarify whether mitochondrial injuries perpetrate the dopaminergic neurotoxicity in HD striatal degeneration. Since Cdk5 has been proposed as a critical regulator of mitochondrial fission (Meuer et al., 2007) and as a deleterious player in the striatal vulnerability upon dopamine signalling (Paoletti et al., 2008), we hypothesize a new detrimental role for Cdk5 in HD pathology by mediating dopaminergic neurotoxicity through deregulation of mitochondrial dynamic processes. On the other hand, several studies have proposed mitochondrial Ca mishandling as a component of Ca controversial and a conclusive cause remains uncertain. We propose that the propensity of mitochondria to undergo fragmentation in HD could result in the disruption of ER-mitochondria contacts, which are essential for the proper buffering of Ca whether defects in ER-mitochondria associated membranes could be responsible for the alteration of mitochondrial Ca handling in HD. dyshomeostasis in HD. However, the results appear 2+ 2+ by mitochondria. Therefore, the second aim of this study was to investigate
Evaluation of therapeutic targets for the treatment of behavioral alterations and neuropathology in Huntington's disease. The role of histone deacetylase 3 and p75 neurotrophin receptor by Núria Suelves Caballol( )

1 edition published in 2018 in English and held by 1 WorldCat member library worldwide

Huntington's disease (HD) is a rare genetic disorder caused by an aberrant expansion of a CAG trinucleotide in the huntingtin gene (Htt). The neuropathology of the disease is characterized by progressive neuronal dysfunction and degeneration in specific regions within the central nervous system, which causes a triad of symptoms including motor, cognitive and psychiatric features. Current treatments only alleviate some of these symptoms without preventing the inevitable neuropathological progression and, therefore, there is great need for finding new therapies that act at the root of the illness. Transcriptional dysregulation, somatic CAG repeat instability and neurotrophic signaling alterations appear early in HD and have been considered important underlying pathogenic mechanisms. Additionally, it has been recently suggested that HDAC3 and p75NTR could participate in some of these processes. Accordingly, the main aim of this thesis was to evaluate the potential therapeutic benefits of the pharmacological inhibition of HDAC3 and the genetic reduction of p75NTR in a knock-in mouse model of HD, termed HdhQ7/Q111. Our results have demonstrated that the selective inhibition of HDAC3 ameliorates cognitive deficits (motor learning and long-term memory alterations) in HdhQ7/Q111 mice by restoring the neuronal activity- dependent transcription of important memory-related genes, such as Arc and Nr4a2. This effect could be due to an increase in histone acetylation, leading to a relaxed DNA configuration, as well as an increase in CBP acetylation, potentially promoting its transcriptional activity. Besides, we have observed that chronic HDAC3 inhibition suppresses somatic CAG repeat expansions in Htt gene. Results of this thesis have shown that HDAC3 inhibition increases Msh2 acetylation at lysine 73, probably altering its DNA repair activity, which has been involved in promoting somatic CAG repeat length increases. Finally, our results have shown that p75NTR levels are increased in HdhQ7/Q111 mice from symptomatic stages. Interestingly, p75NTR normalization delays the onset of motor coordination alterations, several neuropathological HD hallmarks and the overall neurotrophic signaling imbalance in HdhQ7/Q111 mice, which comprise a reduction of the neurotrophin BDNF, a reduction and disrupted activation of its specific receptor, TrkB, and an overactivation of the p75NTR-dependent JNK signaling pathway. However, normalization of p75NTR levels at late disease stages is not able to prevent the loss of striatal integrity and motor coordination in KI mice. This might be the result of the unstoppable advance of other pathological mechanisms that do not depend on p75NTR expression. Therefore, a pharmacological strategy aimed to reduce the expression or activity of p75NTR in HD could provide some benefits at early stages of the disease but, as the pathogenic process progresses, the benefits would be limited. Collectively, our results have provided further insight into the contribution of transcriptional dysregulation, somatic CAG instability and neurotrophin signaling disturbances to HD neuropathological progression and highlight HDAC3 and p75NTR as promising therapeutic targets to correct these pathogenic mechanisms and ameliorate cognitive and motor behavioral impairments in HD
Dual role of CDK5 on cognitive deficits and striatal vulnerability in Huntington's disease by Elena Alvarez Periel( )

1 edition published in 2018 in English and held by 1 WorldCat member library worldwide

Huntington's disease (HD) is a neurodegenerative disorder caused by an autosomic mutation on the Huntingtin (HTT) coding gene. HD is mainly characterized by the appearance of motor symptoms or choreas, which are associated to the selective degeneration of striatal neurons, and by the presence of cognitive disturbances, which are attributed to alterations in corticostriatal connectivity and to hippocampal dysfunction. For this reason, finding targets involved both on striatal vulnerability and cognitive disturbances, might result in therapeutic strategies able to act simultaneously on HD's motor and cognitive symptoms. In this Thesis we have focused on Cyclin-dependent kinase 5 (Cdk5) as one of these putative targets. Cdk5 acts mainly in the central nervous system, where its activator p35 is expressed, and it plays a major role on synaptic plasticity regulation. In addition, altered Cdk5 activity has been described in several neurodegenerative disorders, including HD, where Cdk5 deregulation has been associated to increased striatal vulnerability to excitotoxicity. Moreover, alteration of Cdk5 activity and/or subcellular distribution has also been linked to neuronal cell cycle re-entry, which has been proposed as a possible mechanism leading to neuronal dysfunction and eventual death in several neurodegenerative conditions. Therefore, on one hand, we aimed to study Cdk5 involvement in cognitive deficits and synaptic plasticity alterations in HD. To this end, we generated a new double mutant mice model which expresses one copy of mutant HTT (mHTT) (knock-in or KI), and is conditionally heterozygous for Cdk5 (Cdk5+/). We described that double mutant mice (KI:Cdk5+/-) presented restored corticostriatal and hippocampal cognitive function when compared to their KI littermates. We also observed that preserved corticostriatal function correlated with recovery of corticostriatal NR2B surface levels, which were reduced in KI mice. Moreover, recovery of NR2B surface levels was associated to normalization of NR2B total levels and of the pSrc/pNR2B pathway in the cortex of KI:Cdk5+/- mice. On the other hand, preserved hippocampal cognitive function correlated with recovery of CA1 dendritic spine density, as well as, with increased Rac1 activity in KI:Cdk5+/- mice. Restoration of dendritic spine density was also observed in layer V cortical neurons, in a Rac1-independent manner. Finally, we described that KI mice showed reduced physiological p35 plasma membrane levels in the cortex, which was recovered in KI:Cdk5+/- mice, correlating with preferential alteration of Cdk5 substrates phosphorylation levels in this brain region. In sum, our results demonstrate Cdk5 complex and brain region-specific involvement in cognitive deficits appearance and in synaptic alterations in HD. On the other hand, we also assessed whether Cdk5 deregulation might cause cell cycle re-entry of striatal neurons in HD. Cdk5 forms a nuclear complex with p27 and E2F1 in differentiated neurons, thus preventing E2F1 from binding to its coactivator DP1 and from activating transcription of cell cycle progression genes. For this reason, we analysed nuclear levels of Cdk5 and p27, and we observed that KI mice showed reduced Cdk5 and p27 nuclear levels, which could induce neuronal cell cycle re-entry. In agreement, we also observed increased levels of CyclinD1 in the striatum of KI mice since early symptomatic stages, and increased Cdk4 levels at late disease stages. Finally, we observed that NMDA treatment of striatal primary cultures caused a general reduction of cell cycle proteins neuronal expression, and importantly, it altered their subcellular distribution, reducing nuclear localization of the cell cycle inhibitor p27 and inducing nuclear presence of cell cycle progression proteins, E2F1 and Cdk4. Our results also suggested that presence of mHTT might further potentiate NMDA-induced subcellular distribution alteration of cell cycle proteins. Therefore, we suggest that reduction of Cdk5 nuclear levels might induce cell cycle re-entry of striatal neurons, a process which could be favoured by alterations in NMDA receptors activation, present in HD
Multifuncionalidad de la adenosina desaminasa de superficie y de sus proteinas de unión by Silvia Ginés Padrós( Book )

1 edition published in 2000 in Spanish and held by 1 WorldCat member library worldwide

Pyk2 in the amygdala modulates chronic stress sequelae via PSD-95-related micro-structural changes by Enrica Montalban( )

1 edition published in 2019 in English and held by 0 WorldCat member libraries worldwide

 
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Alternative Names
Ginés, S. (Silvia)

Ginés, Silvia

Silvia Ginés onderzoeker

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