Papel fisiopatológico del factor de respuesta a hipoxia HIF2'alpha' mediante el control del transportador de aminoácidos SLC7A5 y el regulador de síntesis proteica mTORC1

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Medicina. Fecha de lectura: 29 de Octubre de 2013

Huntington's disease-specific mis-splicing unveils key effector genes and altered splicing factors

Correction of mis-splicing events is a growing therapeutic approach for neurological diseases such as spinal muscular atrophy or neuronal ceroid lipofuscinosis 7, which are caused by splicing-affecting mutations. Mis-spliced effector genes that do not harbour mutations are also good candidate therapeutic targets in diseases with more complex aetiologies such as cancer, autism, muscular dystrophies or neurodegenerative diseases. Next-generation RNA sequencing (RNA-seq) has boosted investigation of global mis-splicing in diseased tissue to identify such key pathogenic mis-spliced genes. Nevertheless, while analysis of tumour or dystrophic muscle biopsies can be informative on early stage pathogenic mis-splicing, for neurodegenerative diseases, these analyses are intrinsically hampered by neuronal loss and neuroinflammation in post-mortem brains. To infer splicing alterations relevant to Huntington's disease pathogenesis, here we performed intersect-RNA-seq analyses of human post-mortem striatal tissue and of an early symptomatic mouse model in which neuronal loss and gliosis are not yet present. Together with a human/mouse parallel motif scan analysis, this approach allowed us to identify the shared mis-splicing signature triggered by the Huntington's disease-causing mutation in both species and to infer upstream deregulated splicing factors. Moreover, we identified a plethora of downstream neurodegeneration-linked mis-spliced effector genes that-together with the deregulated splicing factors-become new possible therapeutic targets. In summary, here we report pathogenic global mis-splicing in Huntington's disease striatum captured by our new intersect-RNA-seq approach that can be readily applied to other neurodegenerative diseases for which bona fide animal models are available.Extremadura Research Centre for Advanced Technologies (CETA-CIEMAT), funded by the European Regional Development Fund (ERDF). CETA-CIEMAT belongs to CIEMAT and the Government of Spai

Induction of the mitochondrial NDUFA4L2 protein by HIF-1α decreases oxygen consumption by inhibiting complex i activity

The fine regulation of mitochondrial function has proved to be an essential metabolic adaptation to fluctuations in oxygen availability. During hypoxia, cells activate an anaerobic switch that favors glycolysis and attenuates the mitochondrial activity. This switch involves the hypoxia-inducible transcription factor-1 (HIF-1). We have identified a HIF-1 target gene, the mitochondrial NDUFA4L2 (NADH dehydrogenase [ubiquinone] 1 alpha subcomplex, 4-like 2). Our results, obtained employing NDUFA4L2-silenced cells and NDUFA4L2 knockout murine embryonic fibroblasts, indicate that hypoxia-induced NDUFA4L2 attenuates mitochondrial oxygen consumption involving inhibition of Complex I activity, which limits the intracellular ROS production under low-oxygen conditions. Thus, reducing mitochondrial Complex I activity via NDUFA4L2 appears to be an essential element in the mitochondrial reprogramming induced by HIF-1This work was supported by Ministerio de Ciencia e Innovación (SAF 2007-06592, SAF2010-14851), Comunidad Autónoma de Madrid (SAL 2006/ 0311), Metoxia Project-Health (F2 2009-222741), and Recava Network (RD 06/0014/0031) to M.O.L.; PS09/00101 and CP07/00143 to A.M.-R.; PI060701, PS09/00116, and CP08/00204 to S.C.; BFU2008-03407/BMC to J.A.; SAF2009-08007 to J.A.E.; and CSD2007-00020 to A.M.-R. and J.A.E. The CNIC is supported by the Instituto de Salud Carlos III-MICINN and the Pro-CNIC Foundation. We are grateful to Mike Murphy (Mitochondrial Biology Unit, MRC, Cambridge, UK) for the gift of MitoQ. We also thank Stephen Y. Chan and Joseph Loscalzo (Harvard Medical School, Boston, MA) for providing us ISCU expression vector

CPEB alteration and aberrant transcriptome-polyadenylation lead to a treatable SLC19A3 deficiency in Huntington's disease

Huntington’s disease (HD) is a hereditary neurodegenerative disorder of the basal ganglia for which disease-modifying treatments are not yet available. Although gene-silencing therapies are currently being tested, further molecular mechanisms must be explored to identify druggable targets for HD. Cytoplasmic polyadenylation element binding proteins 1 to 4 (CPEB1 to CPEB4) are RNA binding proteins that repress or activate translation of CPE-containing transcripts by shortening or elongating their poly(A) tail. Here, we found increased CPEB1 and decreased CPEB4 protein in the striatum of patients and mouse models with HD. This correlated with a reprogramming of polyadenylation in 17.3% of the transcriptome, markedly affecting neurodegeneration-associated genes including PSEN1, MAPT, SNCA, LRRK2, PINK1, DJ1, SOD1, TARDBP, FUS, and HTT and suggesting a new molecular mechanism in neurodegenerative disease etiology. We found decreased protein content of top deadenylated transcripts, including striatal atrophy–linked genes not previously related to HD, such as KTN1 and the easily druggable SLC19A3 (the ThTr2 thiamine transporter). Mutations in SLC19A3 cause biotin-thiamine–responsive basal ganglia disease (BTBGD), a striatal disorder that can be treated with a combination of biotin and thiamine. Similar to patients with BTBGD, patients with HD demonstrated decreased thiamine in the cerebrospinal fluid. Furthermore, patients and mice with HD showed decreased striatal concentrations of thiamine pyrophosphate (TPP), the metabolically active form of thiamine. High-dose biotin and thiamine treatment prevented TPP deficiency in HD mice and attenuated the radiological, neuropathological, and motor HD-like phenotypes, revealing an easily implementable therapy that might benefit patients with HD

Investigación del concepto del design thinking y aplicación de la metodología en el diseño de producto

El proyecto se basa en el estudio del concepto de design thinking. Para ello se divide en dos partes. En la primera se investiga la metodología del design thinking y las diferentes técnicas que existen para llevarlo a cabo. En la segunda parte se realiza su puesta en práctica. Para ello se utilizan algunas de las técnicas que ésta ofrece para diseñar el concepto de unas gafas de sol deportivas.Elorza Elorza, A. (2014). Investigación del concepto del design thinking y aplicación de la metodología en el diseño de producto. Universitat Politècnica de València. http://hdl.handle.net/10251/62524Archivo delegad

P2X7 Receptor Upregulation in Huntington’s Disease Brains

Huntington’s disease (HD) is a fatal degenerative disorder affecting the nervous system. It is characterized by motor, cognitive, and psychiatric dysfunctions, with a late onset and an autosomal dominant pattern of inheritance. HD-causing mutation consists in an expansion of repeated CAG triplets in the huntingtin gene (HTT), encoding for an expanded polyglutamine (polyQ) stretch in the huntingtin protein (htt). The mutation causes neuronal dysfunction and loss through multiple mechanisms, affecting both the nucleus and cytoplasm. P2X7 receptor (P2X7R) emerged as a major player in neuroinflammation, since ATP – its endogenous ligand – is massively released under this condition. Indeed, P2X7R stimulation in the central nervous system (CNS) is known to enhance the release of pro-inflammatory cytokines from microglia and of neurotransmitters from neuronal presynaptic terminals, as well as to promote apoptosis. Previous experiments performed with neurons expressing the mutant huntingtin and exploiting HD mouse models demonstrated a role of P2X7R in HD. On the basis of those results, here, we explore for the first time the status of P2X7R in HD patients’ brain. We report that in HD postmortem striatum, as earlier observed in HD mice, the protein levels of the full-length form of P2X7R, also named P2X7R-A, are upregulated. In addition, the exclusively human naturally occurring variant lacking the C-terminus region, P2X7R-B, is upregulated as well. As we show here, this augmented protein levels can be explained by elevated mRNA levels. Furthermore, in HD patients’ striatum, P2X7R shows not only an augmented total transcript level but also an alteration of its splicing. Remarkably, P2X7R introns 10 and 11 are more retained in HD patients when compared with controls. Taken together, our data confirm that P2X7R is altered in brains of HD subjects and strengthen the notion that P2X7R may represent a potential therapeutic target for HD.ISCIII-CiberNed 368 collaborative grants PI2015-2/06-3 and PI2018/06-1 and by MINECO/MCIU grants SAF2015-65371-R 369 (MINECO/AEI/FEDER, UE) and RTI2018-096322-B-I00 (MCIU/AEI/FEDER, UE). AE is recipient of a 370 Juan de la Cierva contract from MINECO/MCIU. CBMSO is also funded by an institutional grant from 371 Fundación Ramón Arece

Latinamerican and maghrebian women migratory process and psychological adjustment: from a gender point of view

[ES]En el presente trabajo se describe el proceso migratorio y el ajuste psicológico de las mujeres inmigrantes que residen en el País Vasco. Se analiza el nivel de estrés percibido y su asociación con variables psicosociales desde la perspectiva de género. La muestra está compuesta por 206 mujeres inmigrantes, el 61,2% de países de Latinoamérica y el 38,8% del Magreb. En general, el balance que realizan sobre el proceso migratorio y su bienestar es positivo, sin embargo, las dificultades derivadas de este proceso, y todos los cambios que supone la inmigración, influye en el ajuste psicológico de las mujeres inmigrantes. Se comprueba que el estrés percibido viene explicado, en parte por la influencia del mismo proceso migratorio, el nivel formativo, la condición residencial y el balance de su situación, elementos atravesados por factores como el género y/o el grupo cultural de pertenencia.[EN]This study examines the migratory process and psychological adjustment of immigrant women currently residing in the Basque Country. Perceived stress is analyzed in relationship with relevant psychosocial variables from a gender perspective. The sample consisted of 206 immigrant women, proceeding from Latin America (61.2%) and Maghreb (38.8%). The participants’ self-assessment of migratory and well-being was in overall positive, however, the diffi culties derived from this process, and the migratory changes, influence the psychological adjustment of immigrant women. Results revealed that perceived stress is affected by the migratory process, educational level, residential status, and the balance of their situation, the elements crossed by factors as gender and/or cultural origin

Altered frontal white matter asymmetry and its implications for cognition in schizophrenia: A tractography study

Background: White matter (WM) alterations are well documented in schizophrenia. Abnormalities in interhemispheric fibers appear to account for altered WM asymmetry in the illness. However, the regional specificity (e.g., frontal versus occipital) of these alterations and their potential contribution to cognitive dysfunction in schizophrenia remain unknown. Methods: Forty one patients with schizophrenia and 21 healthy controls (HC) underwent diffusion-weighted imaging on a 3 Tesla MRI machine. Tract-based spatial statistic (FSL) was used to assess whole brain differences in WM. Probabilistic tractography was performed in order to separately measure frontal and occipital WM tracts. Participants also completed tests of verbal memory and processing speed. Repeated measures analyses of covariance and Pearson correlation analyses were performed. Results: A significant group x cerebral hemisphere interaction was found for fractional anisotropy (FA) (F(1,17) = 7.03; p = .017; ηp2 = 0.29) and radial diffusivity (RD) (F(1,17) = 4.84; p = .042; ηp2 = 0.22) in the frontal tract of patients versus HC. Healthy controls showed higher mean FA and lower mean RD in the left frontal tract compared to patients, who showed the opposite pattern. In patients with schizophrenia, mean FA and RD in the right frontal tract correlated with verbal memory (r = −0.68, p = .046; r = 0.77, p = .015). Conclusions: Asymmetric WM alterations were found in a frontal tract of patients with schizophrenia. Higher mean FA in the right frontal tract correlated with worse verbal memory performance, suggesting a possible contribution these brain changes to cognitive impairment in schizophrenia. Keywords: Schizophrenia, White matter, Asymmetry, Cognition, Tractography, Neuroimagin

A Neuropsychological Rehabilitation Program for Cognitive Impairment in Psychiatric and Neurological Conditions: A Review That Supports Its Efficacy

Neuropsychological rehabilitation has been the focus of much scientific research over the past decades due to its efficacy in different pathologies. Advances in the neuropsychology field have led to improvements and changes in neuropsychological interventions, which in turn have given rise to different approaches and rehabilitation programs. REHACOP is an integrative neuropsychological rehabilitation program designed by specialist neuropsychologists. With an integrated bottom-up and top-down approach, REHACOP includes neurocognition, social cognition, and daily living tasks hierarchically organized on an increasing level of difficulty. Task arrangement is addressed to maximize improvements and transfer effects into participant’s daily living. To date, REHACOP has been implemented on different clinical samples such as patients with schizophrenia, multiple sclerosis (MS), and Parkinson’s disease (PD). This manuscript presents the efficacy data of REHACOP across these three populations and discusses it in the context of the available literature. Overall, the magnitude of improvements obtained by means of REHACOP ranged from medium to high across samples. These changes were not restricted to specific neurocognitive domains since participants attending the REHACOP program also showed changes in social cognition and daily functioning variables by means of both direct and transfer effects. Results regarding REHACOP’s efficacy in psychiatric and neurological conditions have contributed to expanding the existing evidence about the use of structured neuropsychological rehabilitation. In addition, the results obtained after its implementation highlighted the need and importance of designing and implementing integrative neuropsychological rehabilitation programs that are focused not only on cognition per se but also on participants’ performance in daily living