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1.
Int J Cancer ; 2024 Jul 30.
Artículo en Inglés | MEDLINE | ID: mdl-39077999

RESUMEN

Optimizations are expected in the development of immunotherapy for the treatment of Triple-negative breast cancer (TNBC). We studied the expression of galectin-9 (Gal-9) after irradiation and assessed the differential impacts of its targeting with or without radiotherapy. Tumor resections from TNBC patients who received neoadjuvant radiotherapy revealed higher levels of Gal-9 in comparison to their baseline level, only in non-responder patients. Gal-9 expression was also found to be increased in TNBC tumor biopsies and cell lines after irradiation. We investigated the therapeutic advantage of targeting Gal-9 after radiotherapy in mice. Irradiated 4T1 cells or control non-irradiated 4T1 cells were injected into BALB/c mice. Anti-Gal-9 antibody treatment decreased tumor progression only in mice injected with irradiated 4T1 cells. This proof-of-concept study demonstrates that Gal-9 could be considered as a dynamic biomarker after radiotherapy for TNBC and suggests that Gal-9 induced-overexpression could represent an opportunity to develop new therapeutic strategies for TNBC patients.

3.
Proc Natl Acad Sci U S A ; 108(49): E1349-58, 2011 Dec 06.
Artículo en Inglés | MEDLINE | ID: mdl-22049344

RESUMEN

Carefully designed animal models of genetic risk factors are likely to aid our understanding of the pathogenesis of schizophrenia. Here, we study a mouse strain with a truncating lesion in the endogenous Disc1 ortholog designed to model the effects of a schizophrenia-predisposing mutation and offer a detailed account of the consequences that this mutation has on the development and function of a hippocampal circuit. We uncover widespread and cumulative cytoarchitectural alterations in the dentate gyrus during neonatal and adult neurogenesis, which include errors in axonal targeting and are accompanied by changes in short-term plasticity at the mossy fiber/CA3 circuit. We also provide evidence that cAMP levels are elevated as a result of the Disc1 mutation, leading to altered axonal targeting and dendritic growth. The identified structural alterations are, for the most part, not consistent with the growth-promoting and premature maturation effects inferred from previous RNAi-based Disc1 knockdown. Our results provide support to the notion that modest disturbances of neuronal connectivity and accompanying deficits in short-term synaptic dynamics is a general feature of schizophrenia-predisposing mutations.


Asunto(s)
Axones/metabolismo , Hipocampo/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Plasticidad Neuronal , Potenciales de Acción , Animales , Animales Recién Nacidos , Proliferación Celular , Células Cultivadas , AMP Cíclico/metabolismo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Dendritas/metabolismo , Dendritas/fisiología , Giro Dentado/citología , Giro Dentado/crecimiento & desarrollo , Giro Dentado/metabolismo , Hipocampo/citología , Hipocampo/crecimiento & desarrollo , Inmunohistoquímica , Potenciación a Largo Plazo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Fibras Musgosas del Hipocampo/metabolismo , Proteínas del Tejido Nervioso/genética , Neurogénesis , Neuronas/citología , Neuronas/metabolismo , Neuronas/fisiología , Técnicas de Placa-Clamp
4.
Life (Basel) ; 14(2)2024 Feb 09.
Artículo en Inglés | MEDLINE | ID: mdl-38398753

RESUMEN

Schizophrenia (SZ) is a heterogeneous and debilitating psychiatric disorder with a strong genetic component. To elucidate functional networks perturbed in schizophrenia, we analysed a large dataset of whole-genome studies that identified SNVs, CNVs, and a multi-stage schizophrenia genome-wide association study. Our analysis identified three subclusters that are interrelated and with small overlaps: GO:0007017~Microtubule-Based Process, GO:00015629~Actin Cytoskeleton, and GO:0007268~SynapticTransmission. We next analysed three distinct trio cohorts of 75 SZ Algerian, 45 SZ French, and 61 SZ Japanese patients. We performed Illumina HiSeq whole-exome sequencing and identified de novo mutations using a Bayesian approach. We validated 88 de novo mutations by Sanger sequencing: 35 in French, 21 in Algerian, and 32 in Japanese SZ patients. These 88 de novo mutations exhibited an enrichment in genes encoding proteins related to GO:0051015~actin filament binding (p = 0.0011) using David, and enrichments in GO: 0003774~transport (p = 0.019) and GO:0003729~mRNA binding (p = 0.010) using Amigo. One of these de novo variant was found in CORO1C coding sequence. We studied Coro1c haploinsufficiency in a Coro1c+/- mouse and found defects in the corpus callosum. These results could motivate future studies of the mechanisms surrounding genes encoding proteins involved in transport and the cytoskeleton, with the goal of developing therapeutic intervention strategies for a subset of SZ cases.

5.
Hum Mol Genet ; 19(14): 2841-57, 2010 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-20457675

RESUMEN

The SMARCA2 gene, which encodes BRM in the SWI/SNF chromatin-remodeling complex, was recently identified as being associated with schizophrenia (SZ) in a genome-wide approach. Polymorphisms in SMARCA2, associated with the disease, produce changes in the expression of the gene and/or in the encoded amino acid sequence. We show here that an SWI/SNF-centered network including the Smarca2 gene is modified by the down-regulation of REST/NRSF in a mouse neuronal cell line. REST/NRSF down-regulation also modifies the levels of Smarce1, Smarcd3 and SWI/SNF interactors (Hdac1, RcoR1 and Mecp2). Smarca2 down-regulation generates an abnormal dendritic spine morphology that is an intermediate phenotype of SZ. We further found that 8 (CSF2RA, HIST1H2BJ, NOTCH4, NRGN, SHOX, SMARCA2, TCF4 and ZNF804A) out of 10 genome-wide supported SZ-associated genes are part of an interacting network (including SMARCA2), 5 members of which encode transcription regulators. The expression of 3 (TCF4, SMARCA2 and CSF2RA) of the 10 genome-wide supported SZ-associated genes is modified when the REST/NRSF-SWI/SNF chromatin-remodeling complex is experimentally manipulated in mouse cell lines and in transgenic mouse models. The REST/NRSF-SWI/SNF deregulation also results in the differential expression of genes that are clustered in chromosomes suggesting the induction of genome-wide epigenetic changes. Finally, we found that SMARCA2 interactors and the genome-wide supported SZ-associated genes are considerably enriched in genes displaying positive selection in primates and in the human lineage which suggests the occurrence of novel protein interactions in primates. Altogether, these data identify the SWI/SNF chromatin-remodeling complex as a key component of the genetic architecture of SZ.


Asunto(s)
Redes Reguladoras de Genes/fisiología , Primates/genética , Proteínas Represoras/genética , Esquizofrenia/genética , Factores de Transcripción/genética , Animales , Células Cultivadas , Ensamble y Desensamble de Cromatina/genética , Evolución Molecular , Regulación de la Expresión Génica , Estudio de Asociación del Genoma Completo , Humanos , Ratones , Ratones Transgénicos , Modelos Biológicos , Análisis de Secuencia por Matrices de Oligonucleótidos , Filogenia , Proteínas Represoras/metabolismo , Especificidad de la Especie
6.
Life Sci Alliance ; 5(12)2022 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-35914814

RESUMEN

Down syndrome (DS) is caused by human chromosome 21 (HSA21) trisomy. It is characterized by a poorly understood intellectual disability (ID). We studied two mouse models of DS, one with an extra copy of the <i>Dyrk1A</i> gene (189N3) and the other with an extra copy of the mouse Chr16 syntenic region (Dp(16)1Yey). RNA-seq analysis of the transcripts deregulated in the embryonic hippocampus revealed an enrichment in genes associated with chromatin for the 189N3 model, and synapses for the Dp(16)1Yey model. A large-scale yeast two-hybrid screen (82 different screens, including 72 HSA21 baits and 10 rebounds) of a human brain library containing at least 10<sup>7</sup> independent fragments identified 1,949 novel protein-protein interactions. The direct interactors of HSA21 baits and rebounds were significantly enriched in ID-related genes (<i>P</i>-value &lt; 2.29 × 10<sup>-8</sup>). Proximity ligation assays showed that some of the proteins encoded by HSA21 were located at the dendritic spine postsynaptic density, in a protein network at the dendritic spine postsynapse. We located HSA21 DYRK1A and DSCAM, mutations of which increase the risk of autism spectrum disorder (ASD) 20-fold, in this postsynaptic network. We found that an intracellular domain of DSCAM bound either DLGs, which are multimeric scaffolds comprising receptors, ion channels and associated signaling proteins, or DYRK1A. The DYRK1A-DSCAM interaction domain is conserved in <i>Drosophila</i> and humans. The postsynaptic network was found to be enriched in proteins associated with ARC-related synaptic plasticity, ASD, and late-onset Alzheimer's disease. These results highlight links between DS and brain diseases with a complex genetic basis.


Asunto(s)
Enfermedad de Alzheimer , Trastorno del Espectro Autista , Trastorno Autístico , Síndrome de Down , Discapacidad Intelectual , Enfermedad de Alzheimer/genética , Animales , Trastorno del Espectro Autista/genética , Trastorno Autístico/genética , Síndrome de Down/genética , Síndrome de Down/metabolismo , Drosophila , Humanos , Discapacidad Intelectual/genética , Ratones
7.
Hum Mol Genet ; 18(8): 1405-14, 2009 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-19218269

RESUMEN

The molecular mechanisms that lead to the cognitive defects characteristic of Down syndrome (DS), the most frequent cause of mental retardation, have remained elusive. Here we use a transgenic DS mouse model (152F7 line) to show that DYRK1A gene dosage imbalance deregulates chromosomal clusters of genes located near neuron-restrictive silencer factor (REST/NRSF) binding sites. We found that Dyrk1a binds the SWI/SNF complex known to interact with REST/NRSF. The mutation of a REST/NRSF binding site in the promoter of the REST/NRSF target gene L1cam modifies the transcriptional effect of Dyrk1a-dosage imbalance on L1cam. Dyrk1a dosage imbalance perturbs Rest/Nrsf levels with decreased Rest/Nrsf expression in embryonic neurons and increased expression in adult neurons. Using transcriptome analysis of embryonic brain subregions of transgenic 152F7 mouse line, we identified a coordinated deregulation of multiple genes that are responsible for dendritic growth impairment present in DS. Similarly, Dyrk1a overexpression in primary mouse cortical neurons induced severe reduction of the dendritic growth and dendritic complexity. We propose that DYRK1A overexpression-related neuronal gene deregulation via disturbance of REST/NRSF levels, and the REST/NRSF-SWI/SNF chromatin remodelling complex, significantly contributes to the neural phenotypic changes that characterize DS.


Asunto(s)
Ensamble y Desensamble de Cromatina , Proteínas Cromosómicas no Histona/metabolismo , Síndrome de Down/genética , Síndrome de Down/fisiopatología , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Proteínas Represoras/metabolismo , Factores de Transcripción/metabolismo , Animales , Encéfalo/citología , Encéfalo/metabolismo , Células Cultivadas , Dendritas/fisiología , Ratones , Neuronas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Tirosina Quinasas/genética , Transfección , Quinasas DyrK
8.
Pediatr Res ; 69(5 Pt 2): 69R-76R, 2011 May.
Artículo en Inglés | MEDLINE | ID: mdl-21289544

RESUMEN

Attention deficit/hyperactivity disorder (ADHD), a prevalent neurodevelopmental disorder, has been associated with various structural and functional CNS abnormalities but findings about neurobiological mechanisms linking genes to brain phenotypes are just beginning to emerge. Despite the high heritability of the disorder and its main symptom dimensions, common individual genetic variants are likely to account for a small proportion of the phenotype's variance. Recent findings have drawn attention to the involvement of rare genetic variants in the pathophysiology of ADHD, some being shared with other neurodevelopmental disorders. Traditionally, neurobiological research on ADHD has focused on catecholaminergic pathways, the main target of pharmacological treatments. However, more distal and basic neuronal processes in relation with cell architecture and function might also play a role, possibly accounting for the coexistence of both diffuse and specific alterations of brain structure and activation patterns. This article aims to provide an overview of recent findings in the rapidly evolving field of ADHD neurobiology with a focus on novel strategies regarding pathophysiological analyses.


Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad/patología , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Trastorno por Déficit de Atención con Hiperactividad/genética , Encéfalo/patología , Estudio de Asociación del Genoma Completo , Humanos , Fenotipo
9.
Hum Mol Genet ; 17(16): 2541-51, 2008 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-18492799

RESUMEN

Autism spectrum disorders (ASDs) are common, heritable, but genetically heterogeneous neurodevelopmental conditions. We recently defined a susceptibility locus for ASDs on chromosome 1q41-q42. High-resolution single-nucleotide polymorphisms (126 SNPs) genotyping across the chromosome 1q41-q42 region, followed by a MARK1 (microtubule affinity-regulating kinase 1)-tagged-SNP association study in 276 families with autism from the Autism Genetic Research Exchange, showed that several SNPs within the MARK1 gene were significantly associated with ASDs by transmission disequilibrium tests. Haplotype rs12740310*C-rs3737296*G-rs12410279*A was overtransmitted (P(corrected)= 0.0016), with a relative risk for autism of 1.8 in homozygous carriers. Furthermore, ASD-associated SNP rs12410279 modulates the level of transcription of MARK1. We found that MARK1 was overexpressed in the prefrontal cortex (BA46) but not in cerebellar granule cells, on postmortem brain tissues from patients. MARK1 displayed an accelerated evolution along the lineage leading to humans, suggesting possible involvement of this gene in cognition. MARK1 encodes a kinase-regulating microtubule-dependent transport in axons and dendrites. Both overexpression and silencing of MARK1 resulted in significantly shorter dendrite length in mouse neocortical neurons and modified dendritic transport speed. As expected for a gene encoding a key polarity determinant Par-1 protein kinase, MARK1 is involved in axon-dendrite specification. Thus, MARK1 overexpression in humans may be responsible for subtle changes in dendritic functioning.


Asunto(s)
Trastorno Autístico/enzimología , Predisposición Genética a la Enfermedad , Proteínas Serina-Treonina Quinasas/metabolismo , Adolescente , Adulto , Animales , Trastorno Autístico/genética , Trastorno Autístico/fisiopatología , Línea Celular Tumoral , Polaridad Celular , Corteza Cerebelosa/enzimología , Corteza Cerebelosa/fisiopatología , Niño , Preescolar , Mapeo Cromosómico , Cromosomas Humanos Par 1/genética , Dendritas/química , Dendritas/enzimología , Dendritas/fisiología , Evolución Molecular , Femenino , Expresión Génica , Haplotipos , Humanos , Masculino , Ratones , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Proteínas Serina-Treonina Quinasas/genética , Transporte de Proteínas
10.
Med Sci (Paris) ; 26(5): 487-96, 2010 May.
Artículo en Francés | MEDLINE | ID: mdl-20510147

RESUMEN

Attention deficit/hyperactivity disorder (ADHD) is a frequent and disabling condition in school children, with cognitive and behavioral symptoms persisting into adulthood in a majority of patients. Etiology of ADHD is considered multifactorial and heterogenous, with an important contribution of genetic factors. Apart from genetic risk factors, emphasis has been put on the early environment, and prenatal exposure to nicotine, alcohol, prematurity and low birth weight have been associated with subsequent ADHD symptoms. This article reviews recent findings in neurobiology, genetics and neuroimaging of ADHD. Despite their clinical heterogeneity and frequent comorbidities, key symptoms of ADHD, such as impulsivity, hyperactivity and inattention are regularly improved by dopaminergic agonists, leading to consider dopaminergic dysfunction a possibly contributing factor in ADHD. Norepinephrine agonists also have clinical efficacy on ADHD symptoms and several other neurotransmission systems are likely involved in the etiology of ADHD. Dysfunction of neurotransmitter systems have been related to impairments of sustained attention, inhibitory control and working memory. Cognitive tasks focusing on reaction time and verbal working memory fit certain criteria for ADHD endophenotypes, offering a pathway to bridge the gap between observed traits and genetic vulnerability. Despite ADHD being a highly heritable disorder, most candidate genes with replicated findings across association studies only account for a small proportion of genetic variance. Neuroimaging studies using treatment effect or cognitive tasks show differential activation patterns in ADHD patients, with trends towards normalization under treatment. Further insight into neurobiological mechanisms involved in ADHD will arise from collaborative networks and combination of imaging, genetic and neurobiological techniques with consideration of the developmental aspects of ADHD.


Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad/metabolismo , Animales , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Trastorno por Déficit de Atención con Hiperactividad/epidemiología , Trastorno por Déficit de Atención con Hiperactividad/genética , Trastorno por Déficit de Atención con Hiperactividad/patología , Trastorno por Déficit de Atención con Hiperactividad/fisiopatología , Encéfalo/patología , Encéfalo/fisiopatología , Mapeo Encefálico , Niño , Trastornos de la Conducta Infantil/epidemiología , Trastornos de la Conducta Infantil/fisiopatología , Preescolar , Comorbilidad , Diagnóstico por Imagen , Modelos Animales de Enfermedad , Epigénesis Genética , Estudios de Asociación Genética , Humanos , Lactante , Discapacidades para el Aprendizaje/epidemiología , Discapacidades para el Aprendizaje/fisiopatología , Modelos Neurológicos , Modelos Psicológicos , Vías Nerviosas/efectos de los fármacos , Vías Nerviosas/fisiopatología , Neurotransmisores/farmacología , Neurotransmisores/fisiología , Neurotransmisores/uso terapéutico , Ratas , Factores de Riesgo , Trastornos Relacionados con Sustancias/epidemiología , Trastornos Relacionados con Sustancias/fisiopatología
11.
Neuroreport ; 18(5): 441-6, 2007 Mar 26.
Artículo en Inglés | MEDLINE | ID: mdl-17496800

RESUMEN

Neurite outgrowth involves various molecular mechanisms generating complex brain connections. These mechanisms have been linked to plasticity and learning and are thought to be deregulated in neuropsychiatric diseases. The transcription factor REST/NRSF regulates a subset of genes encoding neurite outgrowth molecules. We demonstrate here the downregulation of Rest/Nrsf expression in a mouse neuroblastoma cell line. This downregulation induced a clear increase in neurite length. Quantitative polymerase chain reaction showed deregulation of the candidate genes L1cam, Elmo2, Ulip1 and Ulip2. These genes are bona fide candidates known to be involved in dendrite and axonal outgrowth. This approach could be adapted to high-throughput techniques for determination of the mammalian neurite outgrowth gene repertoire.


Asunto(s)
Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Plasticidad Neuronal/fisiología , ARN Interferente Pequeño/farmacología , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Animales , Línea Celular Tumoral , Proteínas del Citoesqueleto/metabolismo , Proteínas de la Membrana/metabolismo , Ratones , Proteínas del Tejido Nervioso/metabolismo , Molécula L1 de Adhesión de Célula Nerviosa/metabolismo , Neuritas/efectos de los fármacos , Neuroblastoma/patología , Plasticidad Neuronal/efectos de los fármacos , ARN Mensajero/biosíntesis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Factores de Tiempo , Transfección/métodos
12.
Nat Nanotechnol ; 12(4): 322-328, 2017 05.
Artículo en Inglés | MEDLINE | ID: mdl-27893730

RESUMEN

Brain diseases such as autism and Alzheimer's disease (each inflicting >1% of the world population) involve a large network of genes displaying subtle changes in their expression. Abnormalities in intraneuronal transport have been linked to genetic risk factors found in patients, suggesting the relevance of measuring this key biological process. However, current techniques are not sensitive enough to detect minor abnormalities. Here we report a sensitive method to measure the changes in intraneuronal transport induced by brain-disease-related genetic risk factors using fluorescent nanodiamonds (FNDs). We show that the high brightness, photostability and absence of cytotoxicity allow FNDs to be tracked inside the branches of dissociated neurons with a spatial resolution of 12 nm and a temporal resolution of 50 ms. As proof of principle, we applied the FND tracking assay on two transgenic mouse lines that mimic the slight changes in protein concentration (∼30%) found in the brains of patients. In both cases, we show that the FND assay is sufficiently sensitive to detect these changes.


Asunto(s)
Enfermedad de Alzheimer , Trastorno Autístico , Rastreo Celular/métodos , Hipocampo , Nanodiamantes/química , Neuronas , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Animales , Trastorno Autístico/genética , Trastorno Autístico/metabolismo , Trastorno Autístico/patología , Transporte Biológico Activo/genética , Células Cultivadas , Hipocampo/metabolismo , Hipocampo/patología , Ratones , Ratones Transgénicos , Microscopía Fluorescente/métodos , Microscopía por Video/métodos , Neuronas/metabolismo , Neuronas/patología
13.
Nanoscale ; 5(18): 8466-71, 2013 Sep 21.
Artículo en Inglés | MEDLINE | ID: mdl-23852161

RESUMEN

We report an efficient colloidal synthesis of KTiOPO4 (KTP) nanocrystals with excellent crystallinity and the direct observation of optical second-harmonic generation (SHG) from discrete KTP nanocrystals in neurons cultured from mammalian brain cortex. Direct internalization and monitoring of these nanoparticles was successfully achieved without limitations from cytotoxicity, bleaching and blinking emission.


Asunto(s)
Nanopartículas/química , Neuronas/química , Fosfatos/química , Titanio/química , Animales , Células Cultivadas , Corteza Cerebral/citología , Coloides/química , Colorantes Fluorescentes/química , Ratones , Microscopía Fluorescente , Neuronas/citología
14.
Psychiatr Genet ; 20(6): 298-303, 2010 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-20505556

RESUMEN

OBJECTIVE: The Disrupted-in-Schizophrenia-1 (DISC1) gene is a promising genetic risk factor for major mental illnesses, especially schizophrenia. Several variants encompassing the DISC1 gene have been associated with schizophrenia and specific clinical features. Negative results were nevertheless observed, stratification biases, heterogeneity of the analyzed samples and low statistical power being potentially involved. METHODS: We analyzed four single nucleotide polymorphisms (SNPs), including three non-synonymous SNPs, of DISC1 in two independent samples of trios, from France and Algeria, using family-based association tests to elude statistical limits. RESULTS: In 114 French schizophrenia trios, the C allele of non-synonymous rs6675281/Leu607Phe/C1872T was significantly over-transmitted [odds ratio (OR)=2.3, 95% confidence interval (CI)=1.1-4.4]. This same SNP was also more frequently transmitted in the 100 Algerian schizophrenia trios (OR=2.6, 95% CI=0.9-7.3). In the combined 214 trios, a significant over-transmission of the C allele of rs6675281 to the affected probands was observed (P=0.002), even after correction for multiple testing (P corrected=0.01 OR=2.4 and 95% CI=1.3-4.2). Assessing if a dimension of schizophrenia could be more specifically involved, we found that patients with the C allele had a significantly higher Scale for the Assessment of Negative Symptoms total score (P=0.0002). CONCLUSION: The analysis adds convergent evidence in favor of a significant role of the DISC1 gene as a risk factor for schizophrenia, as present in two different samples, in family trios rather than with a case--control approach, and even when multiple tests are controlled for. We could further potentially attribute this effect to the negative dimension of schizophrenia.


Asunto(s)
Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Genética de Población , Proteínas del Tejido Nervioso/genética , Esquizofrenia/genética , Argelia , Demografía , Familia , Femenino , Francia , Humanos , Masculino , Fenotipo , Polimorfismo de Nucleótido Simple/genética , Adulto Joven
15.
Hum Mol Genet ; 16(24): 3047-58, 2007 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-17881655

RESUMEN

Fragile X mental retardation 1 protein (FMRP) is an RNA-binding protein whose absence results in the fragile X syndrome, the most common inherited form of mental retardation. FMRP contains multiple domains with apparently differential affinity to mRNA and interacts also with protein partners present in ribonucleoprotein complexes called RNA granules. In neurons, these particles travel along dendrites and axons to translocate mRNAs to specific destinations in spines and growth cones, where local synthesis of neuro-specific proteins is taking place. However, the molecular mechanisms of how RNA granules are translocated to dendrites remained unknown. We report here the identification and characterization of the motor protein KIF3C as a novel FMRP-interacting protein. In addition, using time-lapse videomicroscopy, we studied the dynamics and kinetics of FMRP-containing RNA granules in dendrites and show that a KIF3C dominant-negative impedes their distal transport. We therefore propose that, in addition to modulate the translation of its mRNA targets, FMRP acts also as a molecular adaptor between RNA granules and the neurospecific kinesin KIF3C that powers their transport along neuronal microtubules.


Asunto(s)
Dendritas/metabolismo , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/fisiología , Cinesinas/metabolismo , Complejos Multiproteicos/metabolismo , ARN/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/fisiología , Animales , Células Cultivadas , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/metabolismo , Humanos , Ratones , Microtúbulos/metabolismo , Unión Proteica , Ratas , Distribución Tisular , Técnicas del Sistema de Dos Híbridos
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