31 results on '"María Santos-Galindo"'
Search Results
2. P2X7 Receptor Upregulation in Huntington’s Disease Brains
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Ivana Ollà, María Santos-Galindo, Ainara Elorza, and José J. Lucas
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P2X7 ,purines ,ATP ,Huntington’s disease ,neuroinflammation ,neurodegenerative disease ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
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.
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- 2020
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3. Selective estrogen receptor modulators as brain therapeutic agents
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Maria Ángeles Arévalo, María Santos-Galindo, Natalia Lagunas, Luis M. Garcia-Segura, Lagunas García, Luisa Natalia, Azcoitia Elías, Íñigo, Maria Ángeles Arévalo, María Santos-Galindo, Natalia Lagunas, Luis M. Garcia-Segura, Lagunas García, Luisa Natalia, and Azcoitia Elías, Íñigo
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Selective estrogen receptor modulators (SERMs), used for the treatment of breast cancer, osteoporosis, and menopausal symptoms, affect the nervous system. Some SERMs trigger neuroprotective mechanisms and reduce neural damage in different experimental models of neural trauma, brain inflammation, neurodegenerative diseases, cognitive impairment, and affective disorders. New SERMs with specific actions on neurons and glial cells may represent promising therapeutic tools for the brain., Depto. de Medicina Legal, Psiquiatría y Patología, Fac. de Medicina, TRUE, pub
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- 2024
4. Pathogenic Mis-splicing of CPEB4 in Schizophrenia
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Ivana Ollà, Antonio F. Pardiñas, Alberto Parras, Ivó H. Hernández, María Santos-Galindo, Sara Picó, Luis F. Callado, Ainara Elorza, Claudia Rodríguez-López, Gonzalo Fernández-Miranda, Eulàlia Belloc, James T.R. Walters, Michael C. O’Donovan, Raúl Méndez, Claudio Toma, J. Javier Meana, Michael J. Owen, and José J. Lucas
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Biological Psychiatry - Published
- 2023
5. Pathogenic mis-splicing of CPEB4 in schizophrenia
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Ivana Ollà, Antonio F. Pardiñas, Alberto Parras, Ivó H. Hernández, María Santos-Galindo, Sara Picó, Luis F. Callado, Ainara Elorza, Gonzalo Fernández-Miranda, Eulàlia Belloc, James T.R. Walters, Michael C. O’Donovan, Claudio Toma, Raúl Méndez, J. Javier Meana, Michael J. Owen, and José J. Lucas
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Schizophrenia (SCZ) is caused by a complex interplay of polygenic risk and environmental factors, which might alter regulators of gene expression leading to pathogenic mis-expression of SCZ risk genes. The RNA binding protein family CPEB (CPEB1, CPEB2, CPEB3, CPEB4) regulates the translation of target RNAs bearing CPE sequences in their 3’UTR (approximately 40% of overall genes). We previously identified CPEB4 as a key dysregulated translational regulator in autism spectrum disorder (ASD), proving that its neuronal-specific microexon (exon 4) is mis-spliced in brains of ASD probands, leading to concerted underexpression of a plethora of high confidence ASD-risk genes. The genetic and pathogenic mechanisms shared between SCZ and ASD make it plausible that mis-splicing of CPEB4 might occur also in SCZ patients, leading to downstream altered brain expression of multiple SCZ-related genes. In this study, we first analyzed Psychiatric Genomics Consortium GWAS data and found significant enrichment of SCZ-associated genes for CPEB4-binder transcripts. We also found decreased inclusion of CPEB4 microexon in postmortem prefrontal cortex of SCZ probands. This mis-splicing is associated with decreased protein levels of SCZ-associated genes that are targets of CPEB4. Interestingly, this happens specifically in individuals with low exposure to antipsychotic medication. Finally, we show that mild overexpression of a CPEB4 transcript lacking exon 4 (CPEB4Δ4) in mice suffices to induce decreased protein levels of SCZ genes targeted by CPEB4; these mice are also characterized by SCZ-linked behaviors. In summary, this study identifies aberrant CPEB4 splicing and downstream mis-expression of SCZ-risk genes as a novel etiological mechanism in SCZ.
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- 2022
6. CPEB alteration and aberrant transcriptome-polyadenylation lead to a treatable SLC19A3 deficiency in Huntington’s disease
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Laura Martí-Sánchez, Belén Pérez, Isidro Ferrer, Sara Picó, Daniel Macías-García, Juan José Garrido, Raúl Méndez, Héctor Anta, Ivó H. Hernández, María Santos-Galindo, Rafael Artuch, Nan Wang, Pilar Navarro, Enrique Fraga, Teresa Iglesias, Margarita Castro, Eulàlia Belloc, Félix Hernández, Alberto Parras, Ainara Elorza, Pablo Mir, X. William Yang, José Luis López-Sendón, Paula Garcia-Esparcia, José J. Lucas, Julia Pose-Utrilla, Instituto de Salud Carlos III, Ministerio de Economía y Competitividad (España), European Commission, Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), Banco Santander, Fundación Ramón Areces, Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (España), Ministerio de Ciencia, Innovación y Universidades (España), Ministerio de Economía y Empresa (España), Fundación Botín, and Fundación BBVA
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Polyadenylation ,Disease ,Bioinformatics ,CPEB ,Vitamin B complex ,Transcriptome ,Huntington's disease ,Corea de Huntington ,Basal ganglia ,Vitamines B ,medicine ,Humans ,Hereditary Neurodegenerative Disorder ,ComputingMilieux_MISCELLANEOUS ,mRNA Cleavage and Polyadenylation Factors ,biology ,Membrane Transport Proteins ,food and beverages ,General Medicine ,medicine.disease ,Huntington Disease ,SLC19A3 ,biology.protein ,ComputingMethodologies_DOCUMENTANDTEXTPROCESSING ,Transcription Factors - Abstract
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., This work was supported by CIBERNED-ISCIII collaborative grants 2013/09-2 to J.J.L. and 2015-2/06 and 2018/06-5 to J.J.L. and T.I., grants SAF2015-65371-R (MINECO/AEI/FEDER, UE), and grants from the Spanish Ministry of Science, Innovation and Universities (MINECO/MICINN): RTI2018-096322-B-I00 (MCIU/AEI/FEDER, UE) to J.J.L., SAF2017-88885-R (MINECO/AEI/FEDER, UE) to T.I., BFU2014-54122-P (MINECO/AEI/FEDER, UE) to R.M., and ISCIII-FEDER (PI17/00199; PI20/00625) to P.N. This work was also supported by the European Union FEDER funds, Fundación Botín–Banco Santander through its Santander Universities Global Division and Fundación Ramón Areces. A.P. and S.P. were recipients of FPI fellowships from MICINN/MINECO. A.P. was also hired through CIBERNED. J.P.-U. was contracted by SAF2017-88885-R (MINECO/AEI/FEDER, UE). D.M.-G. was supported by the “Río Hortega” programme (CM18/00142) from ISCIII-FEDER. A.E. was a recipient of Juan de la Cierva contracts from MICINN/MINECO.
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- 2021
7. I03 CPEB alteration and aberrant transcriptome-polyadenylation unveil a treatable vitamin B1 deficiency in huntington’s disease
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Héctor Anta, Raúl Méndez, Sara Picó, María Santos-Galindo, Enrique Fraga, Rafael Artuch, Juan José Garrido, Belén Pérez, Julia Pose-Utrilla, Félix Hernández, Pablo Mir, José Luis López-Sendón, José J. Lucas, Daniel Macías-García, X. William Yang, Paula Garcia-Esparcia, Margarita Castro, Teresa Iglesias, Alberto Parras, Ainara Elorza, Pilar Navarro, Ivó H. Hernández, Nan Wang, Eulàlia Belloc, Isidro Ferrer, and Laura Martí-Sánchez
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Polyadenylation ,Huntington's disease ,Cytoplasmic polyadenylation element ,SLC19A3 ,Neurodegeneration ,biology.protein ,medicine ,Thiamine transporter ,Thiamine ,Biology ,medicine.disease ,CPEB ,Cell biology - Abstract
Background Although promising gene-silencing therapies are being tested for Huntington’s disease (HD), no disease-modifying treatments are available. Thus, study of molecular mechanisms underneath Htt-mutation must continue to identify easily druggable targets. Cytoplasmic polyadenylation element binding proteins 1–4 (CPEB1–4) are RNA-binding proteins that repress or activate translation of CPE-containing transcripts by shortening or elongating their poly(A) tail. Alteration of CPEB-dependent transcriptome polyadenylation has been associated to diseases like cancer, autism and epilepsy. Aims Analyze CPEBs and polyadenylation in HD. Identify easily druggable targets among genes mis-expressed due to altered CPEB-dependent polyadenylation, to assay them in HD mice. Methods a) Western blot and immunostaining of CPEBs in brains of HD patients and mouse models. b) Genome-wide poly(A)-tail analysis through poly(U) chromatography+gene chip. c) status of CPEB targets and related metabolites by western blot and HPLC. d) radiological, neuropathological and behavioural analysis of HD mice receiving target-related treatment. Results There is a CPEB1/4 imbalance in HD striatum with concomitant altered transcriptome polyadenylation affecting many neurodegeneration-linked genes like PSEN1, MAPT, SNCA, LRRK2, PINK1, DJ1, SOD1, TARDBP, FUS and HTT. Among top deadenylated genes was SLC19A3 (ThTr2 thiamine transporter) whose mutation causes biotin+thiamine responsive basal ganglia disease (BTBGD). Decreased ThTr2 in HD and HD mice led us to discover that HD is in part a BTBG-like thiamine deficiency. Remarkably, high dose biotin+thiamine treatment prevented the thiamine deficiency of HD mice and attenuated their radiological, neuropathological and motor phenotypes. Conclusions This study unveils altered polyadenylation as a new molecular mechanism in neurodegeneration uncovering HD as a thiamine deficiency and, therefore, an easy to implement therapy.
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- 2021
8. Differential regulation of Kidins220 isoforms in Huntington's disease
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Julia Pose-Utrilla, Alicia Belmonte-Alfaro, Giampietro Schiavo, José J. Lucas, Ivó H. Hernández, Teresa Iglesias, Ana del Puerto, Lucía García-Guerra, Ana Simón-García, Álvaro Sebastián-Serrano, Miguel R. Campanero, María Santos-Galindo, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Ministerio de Economía y Competitividad (España), Fundación Ramón Areces, Banco Santander, Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (España), Instituto de Salud Carlos III, Wellcome Trust, and European Commission
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Male ,0301 basic medicine ,Kidins220 ,Striatum ,Hippocampus ,Mice ,Exon ,0302 clinical medicine ,Protein Isoforms ,Ankyrin ,Research Articles ,Neurons ,chemistry.chemical_classification ,biology ,Calpain ,General Neuroscience ,Neurodegeneration ,Neurodegenerative Diseases ,Exons ,Middle Aged ,Huntington Disease ,Female ,Protein Binding ,Signal Transduction ,Neurotrophin ,Adult ,Nerve Tissue Proteins ,Neuroprotection ,Pathology and Forensic Medicine ,03 medical and health sciences ,Huntington's disease ,Huntington's disease (HD) ,medicine ,Animals ,Humans ,Excitotoxicity ,Aged ,Membrane Proteins ,medicine.disease ,Corpus Striatum ,Alternative Splicing ,Disease Models, Animal ,030104 developmental biology ,NMDA ,chemistry ,biology.protein ,Neurology (clinical) ,Isoforms ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Huntington's disease (HD) is an inherited progressive neurodegenerative disease characterized by brain atrophy particularly in the striatum that produces motor impairment, and cognitive and psychiatric disturbances. Multiple pathogenic mechanisms have been proposed including dysfunctions in neurotrophic support and calpain-overactivation, among others. Kinase D-interacting substrate of 220 kDa (Kidins220), also known as ankyrin repeat-rich membrane spanning (ARMS), is an essential mediator of neurotrophin signaling. In adult brain, Kidins220 presents two main isoforms that differ in their carboxy-terminal length and critical protein-protein interaction domains. These variants are generated through alternative terminal exon splicing of the conventional exon 32 (Kidins220-C32) and the recently identified exon 33 (Kidins220-C33). The lack of domains encoded by exon 32 involved in key neuronal functions, including those controlling neurotrophin pathways, pointed to Kidins220-C33 as a form detrimental for neurons. However, the functional role of Kidins220-C33 in neurodegeneration or other pathologies, including HD, has not been explored. In the present work, we discover an unexpected selective downregulation of Kidins220-C33, in the striatum of HD patients, as well as in the R6/1 HD mouse model starting at early symptomatic stages. These changes are C33-specific as Kidins220-C32 variant remains unchanged. We also find the early decrease in Kidins220-C33 levels takes place in neurons, suggesting an unanticipated neuroprotective role for this isoform. Finally, using ex vivo assays and primary neurons, we demonstrate that Kidins220-C33 is downregulated by mechanisms that depend on the activation of the protease calpain. Altogether, these results strongly suggest that calpain-mediated Kidins220-C33 proteolysis modulates onset and/or progression of HD., This work was supported by the Spanish Ministerio de Ciencia, Innovación y Universidades (MCIU) grants to T.I. (SAF2017‐88885‐R), J.J.L. (SAF2015‐65371‐R) and M.R.C. (SAF2017‐88881‐R); by B2017/BMD‐3700 NEUROMETAB‐CM (Comunidad de Madrid, Madrid, Spain) to T.I. and institutional grants to CBMSO from Fundación Ramón Areces and Fundación Banco de Santander to J.J.L. T.I. and J.J.L. are also funded by Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED) and CIBERNED cooperative project 2015‐2/06 (Instituto de Salud Carlos III, Spain). GS work was supported by the Wellcome Trust Senior Investigator Award (107116/Z/15/Z), the European Union's Horizon 2020 Research and Innovation programme under grant agreement 739572 and a UK Dementia Research Institute Foundation award. A.S.‐S. was funded by a contract from CIBERNED‐2015‐2/06.
- Published
- 2019
9. Pathogenic SREK1 decrease in Huntington's disease lowers TAF1 mimicking X-linked dystonia parkinsonism
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Manuel Sánchez-Martín, Belén Pintado, José J. Lucas, Maria Jose Perez-Alvarez, Ramón García-Escudero, Verónica Domínguez, Ivó H. Hernández, María Santos-Galindo, Jorge Rubén Cabrera, Instituto de Salud Carlos III, Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), European Commission, and Fundación Ramón Areces
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0301 basic medicine ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Huntingtin ,SREK1 ,Mice, Transgenic ,Biology ,X-Linked Dystonia Parkinsonism ,Splicing ,RNA-binding proteins (RBP) ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Huntington's disease ,RNA interference ,Internal medicine ,mental disorders ,Basal ganglia ,medicine ,Animals ,Humans ,TAF1 ,Histone Acetyltransferases ,Dystonia ,TATA-Binding Protein Associated Factors ,Serine-Arginine Splicing Factors ,Genetic Diseases, X-Linked ,medicine.disease ,Phosphoproteins ,nervous system diseases ,030104 developmental biology ,Endocrinology ,Huntington Disease ,Dystonic Disorders ,Transcription Factor TFIID ,Neurology (clinical) ,Trinucleotide repeat expansion ,030217 neurology & neurosurgery ,SR proteins - Abstract
The Author(s) (2020)., Huntington’s disease and X-linked dystonia parkinsonism are two monogenic basal ganglia model diseases. Huntington’s disease is caused by a polyglutamine-encoding CAG repeat expansion in the Huntingtin (HTT) gene leading to several toxic interactions of both the expanded CAG-containing mRNA and the polyglutamine-containing protein, while X-linked dystonia parkinsonism is caused by a retrotransposon insertion in the TAF1 gene, which decreases expression of this core scaffold of the basal transcription factor complex TFIID. SRSF6 is an RNA-binding protein of the serine and arginine-rich (SR) protein family that interacts with expanded CAG mRNA and is sequestered into the characteristic polyglutamine-containing inclusion bodies of Huntington’s disease brains. Here we report decreased levels of the SRSF6 interactor and regulator SREK1—another SR protein involved in RNA processing—which includes TAF1 as one of its targets. This led us to hypothesize that Huntington’s disease and X-linked dystonia parkinsonism pathogeneses converge in TAF1 alteration. We show that diminishing SRSF6 through RNA interference in human neuroblastoma cells leads to a decrease in SREK1 levels, which, in turn, suffices to cause diminished TAF1 levels. We also observed decreased SREK1 and TAF1 levels in striatum of Huntington’s disease patients and transgenic model mice. We then generated mice with neuronal transgenic expression of SREK1 (TgSREK1 mice) that, interestingly, showed transcriptomic alterations complementary to those in Huntington’s disease mice. Most importantly, by combining Huntington’s disease and TgSREK1 mice we verify that SREK1 overexpression corrects TAF1 deficiency and attenuates striatal atrophy and motor phenotype of Huntington’s disease mice. Our results therefore demonstrate that altered RNA processing upon SREK1 dysregulation plays a key role in Huntington’s disease pathogenesis and pinpoint TAF1 as a likely general determinant of selective vulnerability of the striatum in multiple neurological disorders., This work was supported by CIBERNED-ISCIII collaborative grants PI2015-2/06-3 and PI2018/06-1 and by grants from Spanish Ministry of Economy and Competitiveness/Ministry of Science, Innovation and Universities (MINECO/MCIU/AEI/FEDER, UE): SAF2015-65371-R and RTI2018-096322-B-I00 to J.J.L. and PI18/00263 from the Instituto de Salud Carlos III (Ministry of Economy, Industry and Competitiveness)—cofunded by the European Regional Development Fund—to R.G.-E. and by institutional grant from Fundación Ramón Areces to CBMSO.
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- 2020
10. Faulty splicing and cytoskeleton abnormalities in Huntington's disease
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Ivó H. Hernández, José J. Lucas, Marta Fernández-Nogales, María Santos-Galindo, and Jorge Rubén Cabrera
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0301 basic medicine ,Pathology ,medicine.medical_specialty ,General Neuroscience ,Biology ,medicine.disease ,Phenotype ,Pathology and Forensic Medicine ,Cell biology ,03 medical and health sciences ,Exon ,Splicing factor ,030104 developmental biology ,0302 clinical medicine ,Atrophy ,Huntington's disease ,mental disorders ,RNA splicing ,medicine ,Huntingtin Protein ,Neurology (clinical) ,Tauopathy ,030217 neurology & neurosurgery - Abstract
Huntington's disease (HD) is caused by a CAG-repeat encoding a polyglutamine (polyQ) tract in the huntingtin protein. There is plenty of evidence of polyQ-driven toxicity. However, CAG repeat RNA-driven alteration of splicing has recently been proposed in analogy to CUG-repeat diseases. Here we review the reported alteration of the CAG-repeat associated splicing factor SRSF6 in brains of HD patients and mouse models and how this correlates with altered splicing of, at least, two microtubule-associated proteins in HD, namely MAPT (tau) and MAP2. Regarding tau, altered splicing of exon 10 has been reported, along with increased levels and 4R/3R-tau ratio and detection of tau in a new nuclear rod-shaped histopathological hallmark termed tau nuclear rod (TNR) or tau nuclear indentation (TNI). These findings, together with an attenuation of HD phenotype in R6/1 mice with tau deficiency and subsequent studies showing increased phosphorylation in mouse models and increased levels in CSF of patients, has led to proposing HD as a tauopathy. Regarding MAP2, an increase in its juvenile form and a decrease in total MAP2 together with redistribution from dendrites to soma is observed in HD patients, which may contribute to the dendritic atrophy in HD. Furthermore, MAP2 positive structures filling nuclear indentations have occasionally been found and co-localized with tau. Therefore, altered MAP function with imbalance in tau/MAP2 content could contribute to HD striatal atrophy and dysfunction. Besides, TNIs might be indicative of such MAP abnormalities. TNIs are also found in early pathology Alzheimer's disease and in tauopathy mice over-expressing mutant 4R-tau. This indicates that tau alteration is sufficient for TNI detection, which becomes a marker of increased total tau and/or altered 4R/3R-tau ratio and reporter of pathology-associated nuclear indentations. Altogether, these recent studies suggest that correcting the SRSF6-driven missplicing and/or microtubule-associated imbalance might be of therapeutic value in HD.
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- 2016
11. Tau-positive nuclear indentations in P301S tauopathy mice
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Alberto Rábano, Jesús Merchán-Rubira, Jesús Avila, Isidro Ferrer, Jeroen J.M. Hoozemans, José J. Lucas, Félix Hernández, María Santos-Galindo, and Marta Fernández-Nogales
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0301 basic medicine ,Chemistry ,General Neuroscience ,Immunoelectron microscopy ,Hippocampus ,Frontotemporal lobar degeneration ,Hippocampal formation ,medicine.disease ,Pathology and Forensic Medicine ,Cell biology ,Tubulin binding ,03 medical and health sciences ,Cell nucleus ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,mental disorders ,medicine ,Neurology (clinical) ,Tauopathy ,Neuroscience ,030217 neurology & neurosurgery ,Immunostaining - Abstract
Increased incidence of neuronal nuclear indentations is a well-known feature of the striatum of Huntington's disease (HD) brains and, in Alzheimer's disease (AD), neuronal nuclear indentations have recently been reported to correlate with neurotoxicity caused by improper cytoskeletal/nucleoskeletal coupling. Initial detection of rod-shaped tau immunostaining in nuclei of cortical and striatal neurons of HD brains and in hippocampal neurons of early Braak stage AD led us to coin the term "tau nuclear rods (TNRs)." Although TNRs traverse nuclear space, they in fact occupy narrow cytoplasmic extensions that fill indentations of the nuclear envelope and we will here refer to this histological hallmark as Tau-immunopositive nuclear indentations (TNIs). We reasoned that TNI formation is likely secondary to tau alterations as TNI detection in HD correlates with an increase in total tau, particularly of the isoforms with four tubulin binding repeats (4R-tau). Here we analyze transgenic mice that overexpress human 4R-tau with a frontotemporal lobar degeneration-tau point mutation (P301S mice) to explore whether tau alteration is sufficient for TNI formation. Immunohistochemistry with various tau antibodies, immunoelectron microscopy and double tau-immunofluorescence/DAPI-nuclear counterstaining confirmed that excess 4R-tau in P301S mice is sufficient for the detection of abundant TNIs that fill nuclear indentations. Interestingly, this does not correlate with an increase in the number of nuclear indentations, thus suggesting that excess total tau or an isoform imbalance in favor of 4R-tau facilitates tau detection inside preexisting nuclear indentations but does not induce formation of the latter. In summary, here we demonstrate that tau alteration is sufficient for TNI detection and our results suggest that the neuropathological finding of TNIs becomes a possible indicator of increased total tau and/or increased 4R/3R-tau ratio in the affected neurons apart from being an efficient way to monitor pathology-associated nuclear indentations.
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- 2016
12. Autism-like phenotype and risk gene mRNA deadenylation by CPEB4 mis-splicing
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Vivek Swarup, Neelroop N. Parikshak, José J. Lucas, Ivó H. Hernández, Manuel Irimia, Eulàlia Belloc, Juan Ignacio Díaz-Hernández, Jose Luis Nieto-Gonzalez, Raúl Méndez, Sara Picó, María Santos-Galindo, Daniel H. Geschwind, Pilar Navarro, Alberto Parras, Ainara Elorza, Annie Rodolosse, Rafael Fernández-Chacón, Olga Peñagarikano, Héctor Anta, UAM. Departamento de Biología, Instituto de Salud Carlos III, European Commission, Ministerio de Economía y Competitividad (España), National Institute of Mental Health (Czech Republic), Junta de Andalucía, Generalitat de Catalunya, European Research Council, Fundación Botín, Fundación BBVA, Fundación Ramón Areces, Ministerio de Ciencia e Innovación (España), National Institutes of Health (US), University of California, Larry L. Hillblom Foundation, Simons Foundation, and University of Maryland
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0301 basic medicine ,Male ,Polyadenylation ,genetic structures ,Autism Spectrum Disorder ,General Science & Technology ,Cytoplasmic polyadenylation element ,Transgene ,Autism ,RNA Splicing ,Mice, Transgenic ,Biology ,behavioral disciplines and activities ,Article ,Transcriptome ,03 medical and health sciences ,Mice ,MRNA polyadenylation ,mental disorders ,MD Multidisciplinary ,Animals ,Humans ,Genetic Predisposition to Disease ,RNA, Messenger ,Gene ,Genetics ,Neurons ,Multidisciplinary ,Brain ,RNA-Binding Proteins ,cytoplasmic polyadenylation ,Exons ,Biología y Biomedicina / Biología ,Phenotype ,030104 developmental biology ,RNA splicing ,Female ,Protein Binding - Abstract
Common genetic contributions to autism spectrum disorder (ASD) reside in risk gene variants that individually have minimal effect sizes. As environmental factors that perturb neurodevelopment also underlie idiopathic ASD, it is crucial to identify altered regulators that can orchestrate multiple ASD risk genes during neurodevelopment. Cytoplasmic polyadenylation element binding proteins 1–4 (CPEB1–4) regulate the translation of specific mRNAs by modulating their poly(A)-tails and thereby participate in embryonic development and synaptic plasticity. Here we find that CPEB4 binds transcripts of most high-confidence ASD risk genes. The brains of individuals with idiopathic ASD show imbalances in CPEB4 transcript isoforms that result from decreased inclusion of a neuron-specific microexon. In addition, 9% of the transcriptome shows reduced poly(A)-tail length. Notably, this percentage is much higher for high-confidence ASD risk genes, correlating with reduced expression of the protein products of ASD risk genes. An equivalent imbalance in CPEB4 transcript isoforms in mice mimics the changes in mRNA polyadenylation and protein expression of ASD risk genes and induces ASD-like neuroanatomical, electrophysiological and behavioural phenotypes. Together, these data identify CPEB4 as a regulator of ASD risk genes., This work was supported by grants: ISCIII-CiberNed-PI2013/09 & -PI2015-2/06 (J.J.L., R.F.-C.), FEDER-PI14/00125 & -PI17/00199 (P.N.), MINECO-SAF2012-34177 & -SAF2015-65371-R (J.J.L.), FEDER-BFU2014-54122-P (R.M.), -BFU2014-55076-P (M.I.), -BFU2016-76050-P (R.F.-C.), -SEV-2012-0208 to CRG by European Union FEDER (M.I.); NIMH 5R37 MH060233, 5R01 MH09714 and 5R01 MH100027 (D.H.G.); Junta de Andalucía-P12-CTS-2232 & -CTS-600 (R.F.-C.); Generalitat de Catalunya-2014/SGR/143 (P.N.); ERC-StG-LS2-637591 (M.I.); and from Fundación Botín-Banco Santander/Santander Universities Global Division, Fundación BBVA, and Fundación Ramón Areces. A.P. was recipient of a MICINN FPI-fellowship; N.N.P. was supported by the NRSA F30 MH099886, UCLA Medical Scientist Training Program and V.S. by a Larry Hillblom Postdoctoral Fellowship. We thank the computing facilities of Extremadura Research Centre for Advanced Technologies (CETA-CIEMAT/Government of Spain), which is funded by ERDF. Tissue, biological specimens or data used in this research were obtained from the Autism BrainNet (formerly the Autism Tissue Program), which is sponsored by the Simons Foundation, and the University of Maryland Brain and Tissue Bank (a component of the NIH NeuroBioBank).
- Published
- 2018
13. The neuroprotective transcription factor ATF5 is decreased and sequestered into polyglutamine inclusions in Huntington’s disease
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José J. Lucas, Jesús F. Torres-Peraza, M. Rosario Fernández-Fernández, Eloísa Ramos-Morón, María Santos-Galindo, Ivó H. Hernández, Antonio Miranda-Vizuete, Maria Jose Perez-Alvarez, Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (España), Instituto de Salud Carlos III, Ministerio de Economía y Competitividad (España), Fundación BBVA, and Fundación Ramón Areces
- Subjects
0301 basic medicine ,Apoptosis ,Mice, Transgenic ,UPR ,Biology ,Neuroprotection ,Pathology and Forensic Medicine ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Huntington's disease ,Cell Line, Tumor ,medicine ,Animals ,Humans ,ATF5 ,Caenorhabditis elegans ,Caenorhabditis elegans Proteins ,Transcription factor ,Inclusion Bodies ,Neurons ,Huntingtin Protein ,ATF6 ,Endoplasmic reticulum ,Human brain ,Endoplasmic Reticulum Stress ,medicine.disease ,Activating Transcription Factors ,Neural stem cell ,Disease Models, Animal ,Huntington Disease ,030104 developmental biology ,medicine.anatomical_structure ,MCL1 ,Unfolded protein response ,Cancer research ,Neurology (clinical) ,Peptides ,ER stress ,Huntington’s disease - Abstract
Activating transcription factor-5 (ATF5) is a stress-response transcription factor induced upon different cell stressors like fasting, amino-acid limitation, cadmium or arsenite. ATF5 is also induced, and promotes transcription of anti-apoptotic target genes like MCL1, during the unfolded protein response (UPR) triggered by endoplasmic reticulum stress. In the brain, high ATF5 levels are found in gliomas and also in neural progenitor cells, which need to decrease their ATF5 levels for differentiation into mature neurons or glia. This initially led to believe that ATF5 is not expressed in adult neurons. More recently, we reported basal neuronal ATF5 expression in adult mouse brain and its neuroprotective induction during UPR in a mouse model of status epilepticus. Here we aimed to explore whether ATF5 is also expressed by neurons in human brain both in basal conditions and in Huntington’s disease (HD), where UPR has been described to be partially impaired due to defective ATF6 processing. Apart from confirming that ATF5 is present in human adult neurons, here we report accumulation of ATF5 within the characteristic polyglutamine-containing neuronal nuclear inclusions in brains of HD patients and mice. This correlates with decreased levels of soluble ATF5 and of its antiapoptotic target MCL1. We then confirmed the deleterious effect of ATF5 deficiency in a Caenorhabditis elegans model of polyglutamine-induced toxicity. Finally, ATF5 overexpression attenuated polyglutamine-induced apoptosis in a cell model of HD. These results reflect that decreased ATF5 in HD—probably secondary to sequestration into inclusions—renders neurons more vulnerable to mutant huntingtin-induced apoptosis and that ATF5-increasing interventions might have therapeutic potential for HD., CiberNed-ISCIII collaborative Grants PI2013/09-2 and PI2015-2/06-3 and by grants from Spanish Ministry of Economy and Competitiveness (MINECO): SAF2009-08233 and SAF2015-65371-R to JJL, by Fundación BBVA and by Fundación Ramón Areces
- Published
- 2017
14. Huntington's disease is a four-repeat tauopathy with tau nuclear rods
- Author
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Jorge Rubén Cabrera, Félix Hernández, Isidro Ferrer, Annemieke J.M. Rozemuller, Jesús Avila, Marta Fernández-Nogales, María Santos-Galindo, José J. Lucas, Jeroen J.M. Hoozemans, Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (España), Ministerio de Ciencia e Innovación (España), Ministerio de Economía y Competitividad (España), Fundación Ramón Areces, Pathology, and NCA - neurodegeneration
- Subjects
Mice, Transgenic ,tau Proteins ,Biology ,medicine.disease_cause ,General Biochemistry, Genetics and Molecular Biology ,Mice ,Huntington's disease ,mental disorders ,medicine ,Animals ,Humans ,Protein Isoforms ,RNA, Messenger ,Mice, Knockout ,Serotonin Plasma Membrane Transport Proteins ,Mutation ,Serine-Arginine Splicing Factors ,Parkinsonism ,Alternative splicing ,Brain ,Nuclear Proteins ,RNA-Binding Proteins ,General Medicine ,Phosphoproteins ,medicine.disease ,Molecular biology ,3. Good health ,Chromosome 17 (human) ,Alternative Splicing ,Huntington Disease ,Tauopathies ,Frontotemporal Dementia ,RNA splicing ,Tauopathy ,Frontotemporal dementia - Abstract
An imbalance of tau isoforms containing either three or four microtubule-binding repeats causes frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) in families with intronic mutations in the MAPT gene. Here we report equivalent imbalances at the mRNA and protein levels and increased total tau levels in the brains of subjects with Huntington's disease (HD) together with rod-like tau deposits along neuronal nuclei. These tau nuclear rods show an ordered filamentous ultrastructure and can be found filling the neuronal nuclear indentations previously reported in HD brains. Finally, alterations in serine/arginine-rich splicing factor-6 coincide with tau missplicing, and a role of tau in HD pathogenesis is evidenced by the attenuation of motor abnormalities of mutant HTT transgenic mice in tau knockout backgrounds. © 2014 Nature America, Inc., Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CiberNed–Instituto de Salud Carlos III) and by grants from Ministerio de Ciencia e Innovación (MICINN), Ministerio de Economía y Competitividad (MINECO), Comunidad Autónoma de Madrid, Fundación Ramón Areces
- Published
- 2014
15. Faulty splicing and cytoskeleton abnormalities in Huntington's disease
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Marta, Fernández-Nogales, María, Santos-Galindo, Ivó H, Hernández, Jorge R, Cabrera, and José J, Lucas
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Neurons ,Huntingtin Protein ,Serine-Arginine Splicing Factors ,Brain ,tau Proteins ,Phosphoproteins ,Alternative Splicing ,Disease Models, Animal ,Huntington Disease ,mental disorders ,Animals ,Humans ,RNA Splicing Factors ,Mini‐symposium: Huntington's Disease ,Trinucleotide Repeat Expansion ,Corrigendum ,Microtubule-Associated Proteins ,Cytoskeleton - Abstract
Huntington's disease (HD) is caused by a CAG-repeat encoding a polyglutamine (polyQ) tract in the huntingtin protein. There is plenty of evidence of polyQ-driven toxicity. However, CAG repeat RNA-driven alteration of splicing has recently been proposed in analogy to CUG-repeat diseases. Here we review the reported alteration of the CAG-repeat associated splicing factor SRSF6 in brains of HD patients and mouse models and how this correlates with altered splicing of, at least, two microtubule-associated proteins in HD, namely MAPT (tau) and MAP2. Regarding tau, altered splicing of exon 10 has been reported, along with increased levels and 4R/3R-tau ratio and detection of tau in a new nuclear rod-shaped histopathological hallmark termed tau nuclear rod (TNR) or tau nuclear indentation (TNI). These findings, together with an attenuation of HD phenotype in R6/1 mice with tau deficiency and subsequent studies showing increased phosphorylation in mouse models and increased levels in CSF of patients, has led to proposing HD as a tauopathy. Regarding MAP2, an increase in its juvenile form and a decrease in total MAP2 together with redistribution from dendrites to soma is observed in HD patients, which may contribute to the dendritic atrophy in HD. Furthermore, MAP2 positive structures filling nuclear indentations have occasionally been found and co-localized with tau. Therefore, altered MAP function with imbalance in tau/MAP2 content could contribute to HD striatal atrophy and dysfunction. Besides, TNIs might be indicative of such MAP abnormalities. TNIs are also found in early pathology Alzheimer's disease and in tauopathy mice over-expressing mutant 4R-tau. This indicates that tau alteration is sufficient for TNI detection, which becomes a marker of increased total tau and/or altered 4R/3R-tau ratio and reporter of pathology-associated nuclear indentations. Altogether, these recent studies suggest that correcting the SRSF6-driven missplicing and/or microtubule-associated imbalance might be of therapeutic value in HD.
- Published
- 2016
16. Tau-positive nuclear indentations in P301S tauopathy mice
- Author
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Marta, Fernández-Nogales, María, Santos-Galindo, Jesús, Merchán-Rubira, Jeroen J M, Hoozemans, Alberto, Rábano, Isidro, Ferrer, Jesús, Avila, Félix, Hernández, and José J, Lucas
- Subjects
Cell Nucleus ,Cerebral Cortex ,Neurons ,Microscopy, Confocal ,Mice, Transgenic ,tau Proteins ,Hippocampus ,Immunohistochemistry ,Corpus Striatum ,Disease Models, Animal ,Tauopathies ,mental disorders ,Mutation ,Animals ,Humans ,Frontotemporal Lobar Degeneration ,Microscopy, Immunoelectron ,Research Articles - Abstract
Increased incidence of neuronal nuclear indentations is a well‐known feature of the striatum of Huntington's disease (HD) brains and, in Alzheimer's disease (AD), neuronal nuclear indentations have recently been reported to correlate with neurotoxicity caused by improper cytoskeletal/nucleoskeletal coupling. Initial detection of rod‐shaped tau immunostaining in nuclei of cortical and striatal neurons of HD brains and in hippocampal neurons of early Braak stage AD led us to coin the term “tau nuclear rods (TNRs).” Although TNRs traverse nuclear space, they in fact occupy narrow cytoplasmic extensions that fill indentations of the nuclear envelope and we will here refer to this histological hallmark as Tau‐immunopositive nuclear indentations (TNIs). We reasoned that TNI formation is likely secondary to tau alterations as TNI detection in HD correlates with an increase in total tau, particularly of the isoforms with four tubulin binding repeats (4R‐tau). Here we analyze transgenic mice that overexpress human 4R‐tau with a frontotemporal lobar degeneration‐tau point mutation (P301S mice) to explore whether tau alteration is sufficient for TNI formation. Immunohistochemistry with various tau antibodies, immunoelectron microscopy and double tau‐immunofluorescence/DAPI‐nuclear counterstaining confirmed that excess 4R‐tau in P301S mice is sufficient for the detection of abundant TNIs that fill nuclear indentations. Interestingly, this does not correlate with an increase in the number of nuclear indentations, thus suggesting that excess total tau or an isoform imbalance in favor of 4R‐tau facilitates tau detection inside preexisting nuclear indentations but does not induce formation of the latter. In summary, here we demonstrate that tau alteration is sufficient for TNI detection and our results suggest that the neuropathological finding of TNIs becomes a possible indicator of increased total tau and/or increased 4R/3R‐tau ratio in the affected neurons apart from being an efficient way to monitor pathology‐associated nuclear indentations.
- Published
- 2016
17. Neuroprotective Effects of Progesterone in Chronic Experimental Autoimmune Encephalomyelitis
- Author
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Silvia Giatti, Elisa Ballarini, Luis M. Garcia-Segura, Guido Cavaletti, Donato Calabrese, Marzia Pesaresi, Barbara Viviani, Federico Abbiati, Donatella Caruso, Roberta Rigolio, Roberto Cosimo Melcangi, María Santos-Galindo, and Mariaserena Boraso
- Subjects
medicine.medical_specialty ,Neuroactive steroid ,biology ,Endocrine and Autonomic Systems ,business.industry ,Endocrinology, Diabetes and Metabolism ,Encephalomyelitis ,Multiple sclerosis ,Experimental autoimmune encephalomyelitis ,Isopregnanolone ,medicine.disease ,Neuroprotection ,Myelin basic protein ,Cellular and Molecular Neuroscience ,Endocrinology ,Dihydroprogesterone ,Internal medicine ,medicine ,biology.protein ,business - Abstract
Observations so far obtained in experimental autoimmune encephalomyelitis (EAE) have revealed the promising neuroprotective effects exerted by progesterone (PROG). The findings suggest that this neuroactive steroid may potentially represent a therapeutic tool for multiple sclerosis (MS). However, up to now, the efficacy of PROG has been only tested in the acute phase of the disease, whereas it is well known that MS expresses different features depending on the phase of the disease. Accordingly, we have evaluated the effect of PROG treatment in EAE induced in Dark Agouti rats (i.e. an experimental model showing a protracted relapsing EAE). Data obtained 45 days after EAE induction show that PROG treatment exerts a beneficial effect on clinical score, confirming surrogate parameters of spinal cord damage in chronic EAE (i.e. reactive microglia, cytokine levels, activity of the Na(+) ,K(+) -ATPase pump and myelin basic protein expression). An increase of the levels of dihydroprogesterone and isopregnanolone (i.e. two PROG metabolites) was also observed in the spinal cord after PROG treatment. Taken together, these results indicate that PROG is effective in reducing the severity of chronic EAE and, consequently, may have potential with respect to MS treatment.
- Published
- 2012
18. Selective Oestrogen Receptor Modulators Decrease the Inflammatory Response of Glial Cells
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María Ángeles Arévalo, Luis M. Garcia-Segura, María Santos-Galindo, Yolanda Diz-Chaves, and María José Bellini
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medicine.medical_specialty ,Microglia ,Endocrine and Autonomic Systems ,Endocrinology, Diabetes and Metabolism ,Inflammation ,Biology ,Pharmacology ,Neuroprotection ,Cellular and Molecular Neuroscience ,Endocrinology ,medicine.anatomical_structure ,Selective estrogen receptor modulator ,Internal medicine ,medicine ,Neuroglia ,Raloxifene ,medicine.symptom ,Neuroinflammation ,Tamoxifen ,medicine.drug - Abstract
Neuroinflammation comprises a feature of many neurological disorders that is accompanied by the activation of glial cells and the release of pro-inflammatory cytokines and chemokines. Such activation is a normal response oriented to protect neural tissue and it is mainly regulated by microglia and astroglia. However, excessive and chronic activation of glia may lead to neurotoxicity and may be harmful for neural tissue. The ovarian hormone oestradiol exerts protective actions in the central nervous system that, at least in part, are mediated by a reduction of reactive gliosis. Several selective oestrogen receptor modulators may also exert neuroprotective effects by controlling glial inflammatory responses. Thus, tamoxifen and raloxifene decrease the inflammatory response caused by lipopolysaccharide, a bacterial endotoxin, in mouse and rat microglia cells in vitro. Tamoxifen and raloxifene are also able to reduce microglia activation in the brain of male and female rats in vivo after the peripheral administration of lipopolysaccharide. In addition, tamoxifen decreases the microglia inflammatory response induced by irradiation. Furthermore, treatment with tamoxifen and raloxifene resulted in a significant reduction of the number of reactive astrocytes in the hippocampus of young, middle-aged and older female rats after a stab wound injury. Tamoxifen, raloxifene and the new selective oestrogen receptor modulators ospemifene and bazedoxifene decrease the expression and release of interleukine-6 and interferon-γ inducible protein-10 in cultured astrocytes exposed to lipopolysaccharide. Ospemifene and bazedoxifene exert anti-inflammatory effects in astrocytes by a mechanism involving classical oestrogen receptors and the inhibition of nuclear factor-kappa B p65 transactivation. These data suggest that oestrogenic compounds are candidates to counteract brain inflammation under neurodegenerative conditions by targeting the production and release of pro-inflammatory molecules by glial cells.
- Published
- 2011
19. Role of astroglia in the neuroplastic and neuroprotective actions of estradiol
- Author
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Luis M. Garcia-Segura, María Ángeles Arévalo, María Santos-Galindo, and Iñigo Azcoitia
- Subjects
General Neuroscience ,Neurodegeneration ,Estrogen receptor ,Biology ,medicine.disease ,Neuroprotection ,Astrogliosis ,Neurotrophic factors ,Synaptic plasticity ,medicine ,biology.protein ,Signal transduction ,Aromatase ,Neuroscience ,hormones, hormone substitutes, and hormone antagonists - Abstract
Astrocyte-neuron cross-talk is an essential component of the mechanisms involved in the neuroendocrine and neuroprotective actions of estradiol. Astrocytes express estrogen receptors, show morphological and functional modifications in response to estradiol and participate in the hormonal regulation of synaptic plasticity and neuroendocrine events. In addition, estradiol interferes with the activation of astrocytes under pathological conditions, modulating the release of neurotrophic factors and inflammatory molecules by these cells. Furthermore, under neurodegenerative conditions, astrocytes synthesize estradiol, which acts as a local neuroprotectant. The actions of estradiol on astrocytes can be imitated by selective estrogen receptor modulators. Some of these molecules, which are free of the peripheral risks associated with estrogen therapy, exert estradiol-like anti-inflammatory actions on astrocytes and are potential therapeutic candidates for the control of reactive astrogliosis.
- Published
- 2010
20. Actions of estrogens on glial cells: Implications for neuroprotection
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Iñigo Azcoitia, María-José Bellini, Luis M. Garcia-Segura, María Santos-Galindo, and María Ángeles Arévalo
- Subjects
medicine.medical_specialty ,Cell Survival ,Extracellular glutamate ,Biophysics ,Glutamic Acid ,Brain Edema ,Estrogenic Compounds ,Biochemistry ,Neuroprotection ,Myelin ,Internal medicine ,medicine ,Animals ,Humans ,Remyelination ,Molecular Biology ,Myelin Sheath ,Inflammation ,Neurons ,Microglia ,Chemistry ,Estrogens ,Oligodendroglia ,Neuroprotective Agents ,medicine.anatomical_structure ,Endocrinology ,nervous system ,Selective estrogen receptor modulator ,Astrocytes ,Brain Injuries ,Intercellular Signaling Peptides and Proteins ,Edema formation ,hormones, hormone substitutes, and hormone antagonists - Abstract
Glial cells are directly or indirectly affected by estradiol and by different estrogenic compounds, such as selective estrogen receptor modulators. Acting on oligodendrocytes, astrocytes and microglia, estrogens regulate remyelination, edema formation, extracellular glutamate levels and the inflammatory response after brain injury. In addition, estradiol induces the expression and release of growth factors by glial cells that promote neuronal survival. Therefore, glial cells are important players in the neuroprotective and reparative mechanisms of estrogenic compounds. © 2009 Elsevier B.V.
- Published
- 2010
21. Selective Estrogen Receptor Modulators Decrease Reactive Astrogliosis in the Injured Brain: Effects of Aging and Prolonged Depletion of Ovarian Hormones
- Author
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Yolanda Diz-Chaves, Luis M. Garcia-Segura, Olga Pernía, Iñigo Azcoitia, Paloma Carrero, George E. Barreto, and María Santos-Galindo
- Subjects
Selective Estrogen Receptor Modulators ,Aging ,medicine.medical_specialty ,medicine.drug_class ,Ovariectomy ,Endocrinology ,Internal medicine ,medicine ,Animals ,Vimentin ,Raloxifene ,Rats, Wistar ,Estradiol ,business.industry ,Brain ,Estrogens ,medicine.disease ,Rats ,Astrogliosis ,Tamoxifen ,Gliosis ,Selective estrogen receptor modulator ,Estrogen ,Astrocytes ,Brain Injuries ,Raloxifene Hydrochloride ,Ovariectomized rat ,Female ,medicine.symptom ,business ,medicine.drug ,Hormone - Abstract
After brain injury, astrocytes acquire a reactive phenotype characterized by a series of morphological and molecular modifications, including the expression of the cytoskeletal protein vimentin. Previous studies have shown that estradiol down-regulates reactive astrogliosis. In this study we assessed whether raloxifene and tamoxifen, two selective estrogen receptor modulators, have effects similar to estradiol in astrocytes. We also assessed whether aging and the timing of estrogenic therapy after ovariectomy influence the action of the estrogenic compounds. Four groups of animals were studied: 1) young rats, ovariectomized at 2 months of age; 2) middle-aged rats, ovariectomized at 8 months of age; 3) aged rats, ovariectomized at 18 months of age; and 4) aged rats, ovariectomized at 2 months and sham operated at 18 months of age. Fifteen days after ovariectomy or sham surgery, animals received a stab wound brain injury and the treatment with the estrogenic compounds. The number of vimentin-immunoreactive astrocytes after injury was significantly higher in the hippocampus of aged rats after a long-term ovariectomy compared with aged animals after a short-term ovariectomy and middle-aged rats. In addition, reactive astrocytes were more numerous in the two groups of aged animals than in young animals. Despite these differences, the estrogenic compounds reduced reactive astrogliosis in all animal groups. These findings indicate that estradiol, raloxifene, and tamoxifen are potential candidates for the control of astrogliosis in young and older individuals and after a prolonged depletion of ovarian hormones. Copyright © 2009 by The Endocrine Society.
- Published
- 2009
22. Selective estrogen receptor modulators regulate reactive microglia after penetrating brain injury
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Luis M. Garcia-Segura, George E. Barreto, and María Santos-Galindo
- Subjects
Aging ,medicine.medical_specialty ,Pathology ,Cognitive Neuroscience ,Context (language use) ,Microgliosis ,Neuroprotection ,lcsh:RC321-571 ,Internal medicine ,medicine ,Raloxifene ,Original Research Article ,Brain Injury ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Microglia ,business.industry ,Tamoxifen ,Endocrinology ,medicine.anatomical_structure ,Selective estrogen receptor modulator ,Ovariectomized rat ,business ,Neuroscience ,medicine.drug - Abstract
Following brain injury, microglia assume a reactive-like state and secrete pro-inflammatory molecules that can potentiate damage. A therapeutic strategy that may limit microgliosis is of potential interest. In this context, selective estrogen receptor modulators, such as raloxifene and tamoxifen, are known to reduce microglia activation induced by neuroinflammatory stimuli in young animals. In the present study, we have assessed whether raloxifene and tamoxifen are able to affect microglia activation after brain injury in young and aged animals in time points relevant to clinics, which is hours after brain trauma. Volume fraction of MHC-II(+) microglia was estimated according to the point-counting method of Weibel within a distance of 350 μm from the lateral border of the wound, and cellular morphology was measured by fractal analysis. Two groups of animals were studied: (1) young rats, ovariectomized at 2 months of age; and (2) aged rats, ovariectomized at 18 months of age. Fifteen days after ovariectomy animals received a stab wound brain injury and the treatment with estrogenic compounds. Our findings indicate that raloxifene and tamoxifen reduced microglia activation in both young and aged animals. Although the volume fraction of reactive microglia was found lower in aged animals, this was accompanied by important changes in cell morphology, where aged microglia assume a bushier and hyperplasic aspect when compared to young microglia. These data suggest that early regulation of microglia activation provides a mechanism by which selective estrogen receptors modulators (SERMs) may exert a neuroprotective effect in the setting of a brain trauma.
- Published
- 2014
23. Gonadal hormones and the control of reactive gliosis
- Author
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Luis M. Garcia-Segura, Iñigo Azcoitia, María Ángeles Arévalo, Estefania Acaz-Fonseca, and María Santos-Galindo
- Subjects
Bioquímica ,Central nervous system ,Neurociencias ,Biology ,Parkin ,Proinflammatory cytokine ,Behavioral Neuroscience ,Endocrinology ,medicine ,Animals ,Humans ,Gliosis ,Neuroinflammation ,Microglia ,Endocrine and Autonomic Systems ,Neurodegeneration ,medicine.disease ,medicine.anatomical_structure ,Neuroprotective Agents ,Brain Injuries ,medicine.symptom ,Neuroscience ,Gonadal Hormones ,Hormone ,Signal Transduction - Abstract
This article is part of a Special Issue >Hormones & Neurotrauma>.Astrocytes and microglia respond to central nervous system (CNS) injury with changes in morphology, proliferation, migration and expression of inflammatory regulators. This phenomenon is known as reactive gliosis. Activation of astrocytes and microglia after acute neural insults, such as stroke or traumatic CNS injury, is considered to be an adaptive response that contributes to minimize neuronal damage. However, reactive gliosis may amplify CNS damage under chronic neurodegenerative conditions. Progesterone, estradiol and testosterone have been shown to control reactive gliosis in different models of CNS injury, modifying the number of reactive astrocytes and reactive microglia and the expression of anti-inflammatory and proinflammatory mediators. The actions of gonadal hormones on reactive gliosis involve different mechanisms, including the modulation of the activity of steroid receptors, such as estrogen receptors α and β, the regulation of nuclear factor-κB mediated transcription of inflammatory molecules and the recruitment of the transcriptional corepressor c-terminal binding protein to proinflammatory promoters. In addition, the Parkinson's disease related gene parkin and the endocannabinoid system also participate in the regulation of reactive gliosis by estradiol. The control exerted by gonadal hormones on reactive gliosis may affect the response of neural tissue to trauma and neurodegeneration and may contribute to sex differences in the manifestation of neurodegenerative diseases. However, the precise functional consequences of the regulation of reactive gliosis by gonadal hormones under acute and chronic neurodegenerative conditions are still not fully clarified. © 2012 Elsevier Inc.
- Published
- 2013
24. Multimodal Analysis in Acute and Chronic Experimental Autoimmune Encephalomyelitis
- Author
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Guido Cavaletti, Donatella Caruso, Luis M. Garcia-Segura, María Santos-Galindo, Mariaserena Boraso, Donato Calabrese, Elisa Ballarini, Marzia Pesaresi, Roberto Cosimo Melcangi, Roberta Rigolio, Federico Abbiati, Barbara Viviani, Silvia Giatti, Giatti, S, Boraso, M, Abbiati, F, Ballarini, E, Calabrese, D, Santos Galindo, M, Rigolio, R, Pesaresi, M, Caruso, D, Viviani, B, Cavaletti, G, Garcia Segura, L, and Melcangi, R
- Subjects
Male ,medicine.medical_specialty ,Neuroactive steroid ,Proteolipid protein 1 ,Encephalomyelitis, Autoimmune, Experimental ,CD3 ,medicine.medical_treatment ,Immunology ,Genes, MHC Class II ,Neuroscience (miscellaneous) ,Nuclease Protection Assays ,Real-Time Polymerase Chain Reaction ,Mass Spectrometry ,EAE, assessment ,Myelin ,Ribonucleases ,Internal medicine ,medicine ,Immunology and Allergy ,Animals ,Fluorometry ,Pharmacology ,Neurons ,biology ,Microglia ,business.industry ,Experimental autoimmune encephalomyelitis ,medicine.disease ,Immunohistochemistry ,Myelin basic protein ,Blood Cell Count ,Rats ,medicine.anatomical_structure ,Endocrinology ,Cytokine ,Neutrophil Infiltration ,Acute Disease ,Chronic Disease ,biology.protein ,Disease Progression ,Cytokines ,Steroids ,Sodium-Potassium-Exchanging ATPase ,business ,Myelin Proteins ,Signal Transduction - Abstract
Different experimental autoimmune encephalomyelitis models (EAE) have been developed. However, due to the different experimental conditions applied, observations simultaneously considering different pathological targets are still scarce. Using EAE induced in Dark Agouti rats with syngenic whole spinal cord homogenate suspended in incomplete Freund's adjuvant, we here analyze neurosteroidogenic machinery, cytokine levels, microglial cells, infiltration of inflammatory cells, myelin proteins and Na(+), K(+)-ATPase pump activity in the spinal cord. Data obtained in the acute phase of the disease confirmed that neurological signs were accompanied by the presence of perivascular infiltrating T cells (CD3(+) cells) and activated monocytic/microglial cells (ED1(+) and MHC-II(+)) in the spinal cord. In particular, the number of MHC-II(+) cells was significantly increased in association with increased expression of pro- (i.e., TNF-α, IL-1β) and anti-inflammatory (i.e., TGF-β) cytokines as well as with decreased expression of proteolipid protein and myelin basic protein. During the chronic phase of the disease, the number of MHC-II(+) cells was still increased, although less than in the acute phase. Changes in the number of MHC-II(+) cells were associated with decreased Na(+),K(+)-ATPase enzymatic activity. A general decrease in the levels of neuroactive steroids, with the exception of an increase in tetrahydroprogesterone and 17β-estradiol, was detected in the acute phase. These changes were maintained or reverted in the chronic phase of EAE. In conclusion, we report that modifications in the neuroimmune response in the acute and chronic phases of EAE are associated with specific changes in myelin proteins, Na(+),K(+)-ATPase pump and in the levels of neuroactive steroids.
- Published
- 2013
25. B45 TAU-positive nuclear indentations in P301S tauopathy mice
- Author
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Isidro Ferrer, Alberto Rábano, Jesús Merchán-Rubira, Marta Fernández-Nogales, Jesús Avila, José J. Lucas, Félix Hernández, Jeroen J.M. Hoozemans, and María Santos-Galindo
- Subjects
Genetically modified mouse ,Chemistry ,Immunoelectron microscopy ,Neurotoxicity ,Hippocampal formation ,medicine.disease ,Cell biology ,Tubulin binding ,body regions ,Psychiatry and Mental health ,mental disorders ,medicine ,Surgery ,Neurology (clinical) ,Tauopathy ,Cytoskeleton ,Immunostaining - Abstract
Increased incidence of neuronal nuclear indentations is a well-known feature of the striatum of Huntington’s disease (HD) brains and, in Alzheimer’s disease (AD), neuronal nuclear indentations have recently been reported to correlate with neurotoxicity due to improper cytoskeletal/nucleoskeletal coupling. Initial detection of rod-shaped tau immunostaining in nuclei of cortical and striatal neurons of HD brains and in hippocampal neurons of early Braak stage AD led us to coin the term “tau nuclear rods (TNRs)”. Although TNRs traverse nuclear space, they in fact occupy narrow cytoplasmic extensions that fill indentations of the nuclear envelope and we will here refer to this histological hallmark as Tau-immunopositve nuclear indentations (TNIs). We reasoned that TNI formation is likely secondary to tau alterations as TNI detection in HD correlates with an increase in total tau, particularly of the isoforms with four tubulin binding repeats (4R-tau). Here we analyse transgenic mice that overexpress human 4R-tau with a frontotemporal lobar degeneration-tau point mutation (P301S mice) to explore whether tau alteration is sufficient for TNI formation. Immunohistochemistry with various tau antibodies, immunoelectron microscopy and double tau-immunofluorescence/DAPI-nuclear counterstaining confirmed that excess 4R-tau in P301S mice is sufficient for the detection of abundant TNIs that fill nuclear indentations. Interestingly, this does not correlate with an increase in the number of nuclear indentations, thus suggesting that excess total tau or an isoform imbalance in favour of 4R-tau facilitates tau detection inside preexisting nuclear indentations but does not induce formation of the latter. In summary, here we demonstrate that tau alteration is sufficient for TNI detection and our results suggest that the neuropathological finding of TNIs becomes a possible indicator of increased total tau and/or increased 4R/3R-tau ratio in the affected neurons apart from being an efficient way to monitor pathology-associated nuclear indentations.
- Published
- 2016
26. Sex differences in the inflammatory response of primary astrocytes to lipopolysaccharide
- Author
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María José Bellini, Luis M. Garcia-Segura, Estefania Acaz-Fonseca, and María Santos-Galindo
- Subjects
Testosterone propionate ,medicine.medical_specialty ,lcsh:Medicine ,Inflammation ,lcsh:Physiology ,Gender Studies ,chemistry.chemical_compound ,Endocrinology ,Internal medicine ,medicine ,Translocator protein ,TNFα ,translocator protein 18 kDa ,Testosterone ,IFN-inducible protein 10 ,biology ,lcsh:QP1-981 ,Research ,Steroidogenic acute regulatory protein ,lcsh:R ,Toll-like receptor 4 ,IL6 ,medicine.anatomical_structure ,chemistry ,testosterone ,TLR4 ,biology.protein ,Tumor necrosis factor alpha ,IL1β ,medicine.symptom ,steroidogenic acute regulatory protein ,Astrocyte - Abstract
Background Numerous neurological and psychiatric disorders show sex differences in incidence, age of onset, symptomatology or outcome. Astrocytes, one of the glial cell types of the brain, show sex differences in number, differentiation and function. Since astrocytes are involved in the response of neural tissue to injury and inflammation, these cells may participate in the generation of sex differences in the response of the brain to pathological insults. To explore this hypothesis, we have examined whether male and female astrocytes show a different response to an inflammatory challenge and whether perinatal testosterone influences this response. Methods Cortical astrocyte cultures were prepared from postnatal day 1 (one day after birth) male or female CD1 mice pups. In addition, cortical astrocyte cultures were also prepared from female pups that were injected at birth with 100 μg of testosterone propionate or vehicle. Cultures were treated for 5 hours with medium containing lipopolysaccharide (LPS) or with control medium. The mRNA levels of IL6, interferon-inducible protein 10 (IP10), TNFα, IL1β, Toll-like receptor 4 (TLR4), steroidogenic acute regulatory protein and translocator protein were assessed by quantitative real-time polymerase chain reaction. Statistical significance was assessed by unpaired t-test or by one-way analysis of variance followed by the Tukey post hoc test. Results The mRNA levels of IL6, TNFα and IL1β after LPS treatment were significantly higher in astrocytes derived from male or androgenized females compared to astrocytes derived from control or vehicle-injected females. In contrast, IP10 mRNA levels after LPS treatment were higher in astrocytes derived from control or vehicle-injected females than in those obtained from males or androgenized females. The different response of male and female astrocytes to LPS was due neither to differences in the basal expression of the inflammatory molecules nor to differences in the expression of the LPS receptor TLR4. In contrast, the different inflammatory response was associated with increased mRNA levels of translocator protein, a key steroidogenic regulator, in female astrocytes that were treated with LPS. Conclusions Male and female cortical astrocytes respond differentially to an inflammatory challenge and this may be predetermined by perinatal testosterone exposure., This work was supported by grant BFU2008-02950-C03-01 from the Ministerio de Ciencia e Innovación, Madrid, Spain. MSG is the recipient of a Junta de Ampliación de Estudios (JAE) predoctoral fellowship from Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain. We thank María Mauriño for excellent technical assistance. Publication costs were supported in part by the Society for Women's Health Research.
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- 2011
27. Selective estrogen receptor modulators as brain therapeutic agents
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María Ángeles Arévalo, Natalia Lagunas, Iñigo Azcoitia, Luis M. Garcia-Segura, and María Santos-Galindo
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Selective Estrogen Receptor Modulators ,Nervous system ,Osteoporosis ,Apoptosis ,Inflammation ,Pharmacology ,Affect (psychology) ,Neuroprotection ,Endocrinology ,Breast cancer ,Animals ,Humans ,Medicine ,Cognitive impairment ,Molecular Biology ,Brain Diseases ,Mood Disorders ,business.industry ,Brain ,Neurodegenerative Diseases ,medicine.disease ,Oxidative Stress ,Tamoxifen ,Neuroprotective Agents ,medicine.anatomical_structure ,Receptors, Estrogen ,Selective estrogen receptor modulator ,Brain Injuries ,Raloxifene Hydrochloride ,Encephalitis ,medicine.symptom ,business ,Neuroscience ,hormones, hormone substitutes, and hormone antagonists - Abstract
Selective estrogen receptor modulators (SERMs), used for the treatment of breast cancer, osteoporosis, and menopausal symptoms, affect the nervous system. Some SERMs trigger neuroprotective mechanisms and reduce neural damage in different experimental models of neural trauma, brain inflammation, neurodegenerative diseases, cognitive impairment, and affective disorders. New SERMs with specific actions on neurons and glial cells may represent promising therapeutic tools for the brain. © 2011 Society for Endocrinology.
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- 2011
28. Role of astroglia in the neuroplastic and neuroprotective actions of estradiol
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Iñigo, Azcoitia, María, Santos-Galindo, María A, Arevalo, and Luis M, Garcia-Segura
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Selective Estrogen Receptor Modulators ,Neuronal Plasticity ,Neuroprotective Agents ,Estradiol ,Receptors, Estrogen ,Astrocytes ,Brain Injuries ,Synapses ,Animals ,Gene Expression ,Hippocampus ,Signal Transduction - Abstract
Astrocyte-neuron cross-talk is an essential component of the mechanisms involved in the neuroendocrine and neuroprotective actions of estradiol. Astrocytes express estrogen receptors, show morphological and functional modifications in response to estradiol and participate in the hormonal regulation of synaptic plasticity and neuroendocrine events. In addition, estradiol interferes with the activation of astrocytes under pathological conditions, modulating the release of neurotrophic factors and inflammatory molecules by these cells. Furthermore, under neurodegenerative conditions, astrocytes synthesize estradiol, which acts as a local neuroprotectant. The actions of estradiol on astrocytes can be imitated by selective estrogen receptor modulators. Some of these molecules, which are free of the peripheral risks associated with estrogen therapy, exert estradiol-like anti-inflammatory actions on astrocytes and are potential therapeutic candidates for the control of reactive astrogliosis.
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- 2010
29. B24 Huntington's Disease As A Tauopathy
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Félix Hernández, Marta Fernández-Nogales, Annemieke J.M. Rozemuller, Isidro Ferrer, Jorge Rubén Cabrera, María Santos-Galindo, Jeroen J.M. Hoozemans, José J. Lucas, and J. Avila
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Genetics ,congenital, hereditary, and neonatal diseases and abnormalities ,Huntingtin ,Biology ,medicine.disease ,Myotonic dystrophy ,Frontotemporal dementia and parkinsonism linked to chromosome 17 ,Progressive supranuclear palsy ,Psychiatry and Mental health ,Huntington's disease ,mental disorders ,medicine ,Corticobasal degeneration ,Surgery ,Neurology (clinical) ,Tauopathy ,Trinucleotide repeat expansion - Abstract
Tauopathies are a group of neurodegenerative diseases such as Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick’s disease (PiD), or frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) that are characterised by altered metabolism and deposition of the microtubule associated protein tau. Alternative splicing of tau exon 10 results in tau isoforms containing either three or four microtubule-binding repeats (3R-tau and 4R-tau). Discovery of silence and intronic mutations leading to increased 4R/3R ratio in FTDP-17 affected families revealed that a disbalance in 4R-tau and 3R-tau in favour of the 4R isoform is sufficient to cause neurodegeneration with personality disturbances, dementia and motor dysfunction. Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder characterised by involuntary movements, psychiatric symptoms and dementia that is caused by an expanded CAG repeat in exon 1 of the Huntingtin (HTT) gene. HD thus belongs to the group of dominant trinucleotide repeat diseases that include many other CAG repeat disorders such as the spinocerebellar ataxias SCA1, SCA2, SCA3, SCA6, SCA7, SCA12, SCA17, dentatorubropallidoluysian atrophy (DRPLA) and spinobulbar muscular atrophy (SBMA) as well as the CUG repeat disorders SCA8 and myotonic dystrophy 1 (DM1). A key element in the pathogenesis of the latter is the binding of splicing factors by the mutant CUG transcript, thus leading to alternative splicing aberrations in multiple genes. Intriguingly, CAG repeats have recently been shown to mimic CUG repeats in the misregulation of alternative splicing. Since it has also been very recently reported that aberrant splicing contributes to the generation of the highly toxic short N-terminal species of HTT, it is conceivable that splicing alterations significantly contribute to HD pathogenesis. Here we aim to explore whether the neurodegeneration-causing increase in 4R/3R-tau mRNA ratio occurs in HD by performing quantitative RT-PCR from RNA extracted from striatum and cortex of HD and control subjects.
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- 2014
30. Huntington’s disease-specific mis-splicing captured by human-mouse intersect-RNA-seq unveils pathogenic effectors and reduced splicing factors
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Manuel Irimia, Ainara Elorza, José Luis Sánchez-Trincado, Ivó H. Hernández, Juan Ignacio Díaz-Hernández, Yamile Marquez, Jorge Rubén Cabrera, José J. Lucas, María Santos-Galindo, and Ramón García-Escudero
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0303 health sciences ,Effector ,Alternative splicing ,RNA-Seq ,Computational biology ,Biology ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,Huntington's disease ,Gliosis ,RNA splicing ,medicine ,medicine.symptom ,Gene ,030217 neurology & neurosurgery ,Neuroinflammation ,030304 developmental biology - Abstract
Deregulated alternative splicing has been implicated in a wide range of pathologies. Deep RNA-sequencing has revealed global mis-splicing signatures in multiple human diseases; however, 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 (HD) 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 HD-causing mutation in both species and to infer upstream deregulated splicing factors. Moreover, we identified a plethora of downstream neurodegeneration-linked effector genes, whose aberrant splicing is associated with decreased protein levels in HD patients and mice. In summary, our intersect-RNA-seq approach unveiled the pathogenic contribution of mis-splicing to HD and could be readily applied to other neurodegenerative diseases for which bona fide animal models are available.
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31. Huntington’s disease-specific mis-splicing unveils key effector genes and altered splicing factors
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Ainara Elorza, Juan Ignacio Díaz-Hernández, María Santos-Galindo, Manuel Irimia, José Luis Sánchez-Trincado, Ivó H. Hernández, Yamile Marquez, Ramón García-Escudero, Jorge Rubén Cabrera, Sara Picó, José J. Lucas, Centro Extremeño de Tecnologías Avanzadas, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (España), and Agencia Estatal de Investigación (España)
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0301 basic medicine ,RNA Splicing Factors ,Disease ,Computational biology ,Biology ,RNA-binding proteins (RBP) ,splicing ,Mice ,03 medical and health sciences ,RNA-sequencing (RNA-seq) ,0302 clinical medicine ,Huntington's disease ,medicine ,Animals ,Humans ,Gene ,Huntingtin Protein ,AcademicSubjects/SCI01870 ,Sequence Analysis, RNA ,Effector ,Original Articles ,Spinal muscular atrophy ,medicine.disease ,Corpus Striatum ,3. Good health ,Alternative Splicing ,Huntington Disease ,030104 developmental biology ,splicing factors ,RNA splicing ,RNA ,AcademicSubjects/MED00310 ,Neuronal ceroid lipofuscinosis ,Neurology (clinical) ,Corea de Huntington (Malaltia) ,Proteïnes ,030217 neurology & neurosurgery ,Genètica ,Huntington’s disease - Abstract
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., Elorza et al. reveal a mis-splicing signature in Huntington’s disease patients, devoid of human post-mortem related artefacts by intersecting data with an early symptomatic mouse model. They identify five families of altered splicing factors and six key pathogenic genes, unveiling new targets for therapeutic intervention.
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