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1.
Neurobiol Dis ; 196: 106523, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38705491

RESUMO

Down syndrome (DS) is the most common condition with intellectual disability and is caused by trisomy of Homo sapiens chromosome 21 (HSA21). The increased dosage of genes on HSA21 is associated with early neurodevelopmental changes and subsequently at adult age with the development of Alzheimer-like cognitive decline. However, the molecular mechanisms promoting brain pathology along aging are still missing. The novel Ts66Yah model represents an evolution of the Ts65Dn, used in characterizing the progression of brain degeneration, and it manifest phenotypes closer to human DS condition. In this study we performed a longitudinal analysis (3-9 months) of adult Ts66Yah mice. Our data support the behavioural alterations occurring in Ts66Yah mice at older age with improvement in the detection of spatial memory defects and also a new anxiety-related phenotype. The evaluation of hippocampal molecular pathways in Ts66Yah mice, as effect of age, demonstrate the aberrant regulation of redox balance, proteostasis, stress response, metabolic pathways, programmed cell death and synaptic plasticity. Intriguingly, the genotype-driven changes observed in those pathways occur early promoting altered brain development and the onset of a condition of premature aging. In turn, aging may account for the subsequent hippocampal deterioration that fall in characteristic neuropathological features. Besides, the analysis of sex influence in the alteration of hippocampal mechanisms demonstrate only a mild effect. Overall, data collected in Ts66Yah provide novel and consolidated insights, concerning trisomy-driven processes that contribute to brain pathology in conjunction with aging. This, in turn, aids in bridging the existing gap in comprehending the intricate nature of DS phenotypes.


Assuntos
Envelhecimento , Encéfalo , Modelos Animais de Doenças , Síndrome de Down , Animais , Síndrome de Down/genética , Síndrome de Down/patologia , Síndrome de Down/metabolismo , Envelhecimento/genética , Envelhecimento/patologia , Envelhecimento/fisiologia , Camundongos , Masculino , Encéfalo/metabolismo , Encéfalo/patologia , Feminino , Cognição/fisiologia , Hipocampo/metabolismo , Hipocampo/patologia , Disfunção Cognitiva/genética , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Camundongos Transgênicos
2.
Hum Mol Genet ; 30(9): 771-788, 2021 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-33693642

RESUMO

Down syndrome (DS) is the most common genetic form of intellectual disability caused by the presence of an additional copy of human chromosome 21 (Hsa21). To provide novel insights into genotype-phenotype correlations, we used standardized behavioural tests, magnetic resonance imaging and hippocampal gene expression to screen several DS mouse models for the mouse chromosome 16 region homologous to Hsa21. First, we unravelled several genetic interactions between different regions of chromosome 16 and how they contribute significantly to altering the outcome of the phenotypes in brain cognition, function and structure. Then, in-depth analysis of misregulated expressed genes involved in synaptic dysfunction highlighted six biological cascades centred around DYRK1A, GSK3ß, NPY, SNARE, RHOA and NPAS4. Finally, we provide a novel vision of the existing altered gene-gene crosstalk and molecular mechanisms targeting specific hubs in DS models that should become central to better understanding of DS and improving the development of therapies.


Assuntos
Síndrome de Down , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Cognição , Modelos Animais de Doenças , Síndrome de Down/genética , Síndrome de Down/patologia , Hipocampo/metabolismo , Camundongos , Camundongos Transgênicos
3.
PLoS Genet ; 11(3): e1005062, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25803843

RESUMO

The trisomy of human chromosome 21 (Hsa21), which causes Down syndrome (DS), is the most common viable human aneuploidy. In contrast to trisomy, the complete monosomy (M21) of Hsa21 is lethal, and only partial monosomy or mosaic monosomy of Hsa21 is seen. Both conditions lead to variable physiological abnormalities with constant intellectual disability, locomotor deficits, and altered muscle tone. To search for dosage-sensitive genes involved in DS and M21 phenotypes, we created two new mouse models: the Ts3Yah carrying a tandem duplication and the Ms3Yah carrying a deletion of the Hspa13-App interval syntenic with 21q11.2-q21.3. Here we report that the trisomy and the monosomy of this region alter locomotion, muscle strength, mass, and energetic balance. The expression profiling of skeletal muscles revealed global changes in the regulation of genes implicated in energetic metabolism, mitochondrial activity, and biogenesis. These genes are downregulated in Ts3Yah mice and upregulated in Ms3Yah mice. The shift in skeletal muscle metabolism correlates with a change in mitochondrial proliferation without an alteration in the respiratory function. However, the reactive oxygen species (ROS) production from mitochondrial complex I decreased in Ms3Yah mice, while the membrane permeability of Ts3Yah mitochondria slightly increased. Thus, we demonstrated how the Hspa13-App interval controls metabolic and mitochondrial phenotypes in muscles certainly as a consequence of change in dose of Gabpa, Nrip1, and Atp5j. Our results indicate that the copy number variation in the Hspa13-App region has a peripheral impact on locomotor activity by altering muscle function.


Assuntos
Síndrome de Down/genética , Monossomia/genética , Atividade Motora/genética , Força Muscular/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Cromossomos Humanos Par 21/genética , Modelos Animais de Doenças , Síndrome de Down/fisiopatologia , Metabolismo Energético/genética , Fator de Transcrição de Proteínas de Ligação GA/genética , Humanos , Camundongos , Mitocôndrias Musculares/genética , Mitocôndrias Musculares/patologia , ATPases Mitocondriais Próton-Translocadoras/genética , Monossomia/fisiopatologia , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatologia , Proteínas Nucleares/genética , Proteína 1 de Interação com Receptor Nuclear
4.
PLoS Genet ; 8(5): e1002724, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22693452

RESUMO

Down syndrome (DS) leads to complex phenotypes and is the main genetic cause of birth defects and heart diseases. The Ts65Dn DS mouse model is trisomic for the distal part of mouse chromosome 16 and displays similar features with post-natal lethality and cardiovascular defects. In order to better understand these defects, we defined electrocardiogram (ECG) with a precordial set-up, and we found conduction defects and modifications in wave shape, amplitudes, and durations in Ts65Dn mice. By using a genetic approach consisting of crossing Ts65Dn mice with Ms5Yah mice monosomic for the App-Runx1 genetic interval, we showed that the Ts65Dn viability and ECG were improved by this reduction of gene copy number. Whole-genome expression studies confirmed gene dosage effect in Ts65Dn, Ms5Yah, and Ts65Dn/Ms5Yah hearts and showed an overall perturbation of pathways connected to post-natal lethality (Coq7, Dyrk1a, F5, Gabpa, Hmgn1, Pde10a, Morc3, Slc5a3, and Vwf) and heart function (Tfb1m, Adam19, Slc8a1/Ncx1, and Rcan1). In addition cardiac connexins (Cx40, Cx43) and sodium channel sub-units (Scn5a, Scn1b, Scn10a) were found down-regulated in Ts65Dn atria with additional down-regulation of Cx40 in Ts65Dn ventricles and were likely contributing to conduction defects. All these data pinpoint new cardiac phenotypes in the Ts65Dn, mimicking aspects of human DS features and pathways altered in the mouse model. In addition they highlight the role of the App-Runx1 interval, including Sod1 and Tiam1, in the induction of post-natal lethality and of the cardiac conduction defects in Ts65Dn. These results might lead to new therapeutic strategies to improve the care of DS people.


Assuntos
Precursor de Proteína beta-Amiloide/genética , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Síndrome de Down , Dosagem de Genes , Cardiopatias Congênitas , Animais , Anormalidades Congênitas/genética , Modelos Animais de Doenças , Síndrome de Down/genética , Síndrome de Down/metabolismo , Eletrocardiografia , Regulação da Expressão Gênica , Bloqueio Cardíaco/fisiopatologia , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/fisiopatologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fenótipo
5.
Neurobiol Dis ; 69: 65-75, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24801365

RESUMO

Cognitive deficits in Down syndrome (DS) have been linked to increased synaptic inhibition, leading to an imbalance of excitation/inhibition (E/I). Various mouse models and studies from human brains have implicated an HSA21 gene, the serine/threonine kinase DYRK1A, as a candidate for inducing cognitive dysfunction. Here, consequences of alterations in Dyrk1a dosage were assessed in mouse models with varying copy numbers of Dyrk1a: mBACtgDyrk1a, Ts65Dn and Dp(16)1Yey (with 3 gene copies) and Dyrk1a(+/-) (one functional copy). Molecular (i.e. immunoblotting/immunohistochemistry) and behavioral analyses (e.g., rotarod, Morris water maze, Y-maze) were performed in mBACtgDyrk1a mice. Increased expression of DYRK1A in mBACtgDyrk1a induced molecular alterations in synaptic plasticity pathways, particularly expression changes in GABAergic and glutaminergic related proteins. Similar alterations were observed in models with partial trisomy of MMU16, Ts65Dn and Dp(16)1Yey, and were reversed in the Dyrk1a(+/-) model. Dyrk1a overexpression produced an increased number and signal intensity of GAD67 positive neurons, indicating enhanced inhibition pathways in three different models: mBACtgDyrk1a, hYACtgDyrk1a and Dp(16)1Yey. Functionally, Dyrk1a overexpression protected mice from PTZ-induced seizures related to GABAergic neuron plasticity. Our study shows that DYRK1A overexpression affects pathways involved in synaptogenesis and synaptic plasticity and influences E/I balance toward inhibition. Inhibition of DYRK1A activity offers a therapeutic target for DS, but its inhibition/activation may also be relevant for other psychiatric diseases with E/I balance alterations.


Assuntos
Dosagem de Genes , Aprendizagem , Inibição Neural/genética , Plasticidade Neuronal/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Tirosina Quinases/genética , Animais , Modelos Animais de Doenças , Síndrome de Down/genética , Síndrome de Down/fisiopatologia , Síndrome de Down/psicologia , Humanos , Aprendizagem/fisiologia , Masculino , Memória/fisiologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Atividade Motora/genética , Atividade Motora/fisiologia , Inibição Neural/fisiologia , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Convulsões/genética , Convulsões/fisiopatologia , Sinapses/genética , Sinapses/fisiologia , Quinases Dyrk
6.
Mol Genet Metab ; 110(3): 371-7, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23920041

RESUMO

BACKGROUND AND AIMS: Down syndrome is caused by trisomy of all or part of human chromosome 21. Individuals with Down syndrome present some metabolic abnormalities involving lipoproteins, notably lower high-density lipoprotein levels associated with altered lecithin:cholesterol acyltransferase activity and apolipoprotein A-I levels. DYRK1A is a kinase overexpressed in Down syndrome that can activate the STAT3 pathway, which is involved in lecithin:cholesterol acyltransferase expression. Therefore, we characterized the role of DYRK1A overexpression on lecithin:cholesterol acyltransferase activity and expression in mouse models. METHODS: Effects of Dyrk1a overexpression were examined in mice overexpressing Dyrk1a by ELISA, chemical analyses and Western blotting. RESULTS: Overexpression of DYRK1A decreased plasma lecithin:cholesterol acyltransferase activity and hepatic STAT3 activation, which was associated with activation of SHP2, a tyrosine phosphatase. Although hepatic apolipoprotein E and D levels were increased in mice overexpressing DYRK1A, decreased plasma lecithin:cholesterol acyltransferase activity was associated with decreased hepatic and plasma apolipoprotein A-I levels. High-density lipoprotein-cholesterol levels were also decreased in plasma despite similar total cholesterol and non-high-density lipoprotein-cholesterol levels. CONCLUSIONS: We identified the role of DYRK1A overexpression on altered lipoprotein metabolism.


Assuntos
Apolipoproteína A-I/sangue , Expressão Gênica , Fosfatidilcolina-Esterol O-Aciltransferase/sangue , Proteínas Serina-Treonina Quinases/genética , Proteínas Tirosina Quinases/genética , Animais , Apolipoproteínas D/metabolismo , Apolipoproteínas E/metabolismo , HDL-Colesterol/sangue , Ativação Enzimática , Masculino , Camundongos , Camundongos Transgênicos , Fosforilação , Proteínas Serina-Treonina Quinases/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Proteínas Tirosina Quinases/metabolismo , Fator de Transcrição STAT3/metabolismo , Quinases Dyrk
7.
Dis Model Mech ; 15(12)2022 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-36374158

RESUMO

Down syndrome (DS) is caused by trisomy of human chromosome 21 (Hsa21). The understanding of genotype-phenotype relationships, the identification of driver genes and various proofs of concept for therapeutics have benefited from mouse models. The premier model, named Ts(1716)65Dn/J (Ts65Dn), displayed phenotypes related to human DS features. It carries an additional minichromosome with the Mir155 to Zbtb21 region of mouse chromosome 16, homologous to Hsa21, encompassing around 90 genes, fused to the centromeric part of mouse chromosome 17 from Pisd-ps2/Scaf8 to Pde10a, containing 46 genes not related to Hsa21. Here, we report the investigation of a new model, Ts66Yah, generated by CRISPR/Cas9 without the genomic region unrelated to Hsa21 on the minichromosome. As expected, Ts66Yah replicated DS cognitive features. However, certain phenotypes related to increased activity, spatial learning and molecular signatures were changed, suggesting genetic interactions between the Mir155-Zbtb21 and Scaf8-Pde10a intervals. Thus, Ts66Yah mice have stronger construct and face validity than Ts65Dn mice for mimicking consequences of DS genetic overdosage. Furthermore, this study is the first to demonstrate genetic interactions between triplicated regions homologous to Hsa21 and others unrelated to Hsa21. This article has an associated First Person interview with the first author of the paper.


Assuntos
Síndrome de Down , Humanos , Camundongos , Animais , Síndrome de Down/genética , Diester Fosfórico Hidrolases
8.
Hum Mol Genet ; 18(24): 4756-69, 2009 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-19783846

RESUMO

Mental retardation in Down syndrome (DS), the most frequent trisomy in humans, varies from moderate to severe. Several studies both in human and based on mouse models identified some regions of human chromosome 21 (Hsa21) as linked to cognitive deficits. However, other intervals such as the telomeric region of Hsa21 may contribute to the DS phenotype but their role has not yet been investigated in detail. Here we show that the trisomy of the 12 genes, found in the 0.59 Mb (Abcg1-U2af1) Hsa21 sub-telomeric region, in mice (Ts1Yah) produced defects in novel object recognition, open-field and Y-maze tests, similar to other DS models, but induces an improvement of the hippocampal-dependent spatial memory in the Morris water maze along with enhanced and longer lasting long-term potentiation in vivo in the hippocampus. Overall, we demonstrate the contribution of the Abcg1-U2af1 genetic region to cognitive defect in working and short-term recognition memory in DS models. Increase in copy number of the Abcg1-U2af1 interval leads to an unexpected gain of cognitive function in spatial learning. Expression analysis pinpoints several genes, such as Ndufv3, Wdr4, Pknox1 and Cbs, as candidates whose overexpression in the hippocampus might facilitate learning and memory in Ts1Yah mice. Our work unravels the complexity of combinatorial genetic code modulating different aspect of mental retardation in DS patients. It establishes definitely the contribution of the Abcg1-U2af1 orthologous region to the DS etiology and suggests new modulatory pathways for learning and memory.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Modelos Animais de Doenças , Síndrome de Down/genética , Lipoproteínas/genética , Camundongos , Proteínas Nucleares/genética , Ribonucleoproteínas/genética , Trissomia/genética , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Animais , Ansiedade/genética , Sinapses Elétricas/fisiologia , Comportamento Exploratório , Deleção de Genes , Dosagem de Genes , Duplicação Gênica , Código Genético , Humanos , Aprendizagem , Memória , Camundongos Mutantes , Atividade Motora/genética , Fator de Processamento U2AF
9.
Mamm Genome ; 22(11-12): 674-84, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21953411

RESUMO

Down syndrome (DS) is the most frequent genetic disorder leading to intellectual disabilities and is caused by three copies of human chromosome 21. Mouse models are widely used to better understand the physiopathology in DS or to test new therapeutic approaches. The older and the most widely used mouse models are the trisomic Ts65Dn and the Ts1Cje mice. They display deficits similar to those observed in DS people, such as those in behavior and cognition or in neuronal abnormalities. The Ts65Dn model is currently used for further therapeutic assessment of candidate drugs. In both models, the trisomy was induced by reciprocal chromosomal translocations that were not further characterized. Using a comparative genomic approach, we have been able to locate precisely the translocation breakpoint in these two models and we took advantage of this finding to derive a new and more efficient Ts65Dn genotyping strategy. Furthermore, we found that the translocations introduce additional aneuploidy in both models, with a monosomy of seven genes in the most telomeric part of mouse chromosome 12 in the Ts1Cje and a trisomy of 60 centromeric genes on mouse chromosome 17 in the Ts65Dn. Finally, we report here the overexpression of the newly found aneuploid genes in the Ts65Dn heart and we discuss their potential impact on the validity of the DS model.


Assuntos
Modelos Animais de Doenças , Síndrome de Down/genética , Translocação Genética , Trissomia , Animais , Linhagem Celular , Hibridização Genômica Comparativa , Quebras de DNA , Síndrome de Down/metabolismo , Síndrome de Down/patologia , Duplicação Gênica , Genótipo , Camundongos , Camundongos Endogâmicos BALB C , Mutação , Miocárdio/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos
10.
Genes (Basel) ; 12(11)2021 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-34828439

RESUMO

Down syndrome is the main cause of intellectual disabilities with a large set of comorbidities from developmental origins but also that appeared across life span. Investigation of the genetic overdosage found in Down syndrome, due to the trisomy of human chromosome 21, has pointed to one main driver gene, the Dual-specificity tyrosine-regulated kinase 1A (Dyrk1a). Dyrk1a is a murine homolog of the drosophila minibrain gene. It has been found to be involved in many biological processes during development and in adulthood. Further analysis showed its haploinsufficiency in mental retardation disease 7 and its involvement in Alzheimer's disease. DYRK1A plays a role in major developmental steps of brain development, controlling the proliferation of neural progenitors, the migration of neurons, their dendritogenesis and the function of the synapse. Several strategies targeting the overdosage of DYRK1A in DS with specific kinase inhibitors have showed promising evidence that DS cognitive conditions can be alleviated. Nevertheless, providing conditions for proper temporal treatment and to tackle the neurodevelopmental and the neurodegenerative aspects of DS across life span is still an open question.


Assuntos
Síndrome de Down/genética , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Síndrome de Down/tratamento farmacológico , Síndrome de Down/metabolismo , Humanos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/genética , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/genética , Quinases Dyrk
11.
Br J Pharmacol ; 177(5): 1106-1118, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31652355

RESUMO

BACKGROUND AND PURPOSE: Excessive GABAergic inhibition contributes to cognitive dysfunctions in Down syndrome (DS). Selective negative allosteric modulators (NAMs) of α5-containing GABAA receptors such as the α5 inverse agonist (α5IA) restore learning and memory deficits in Ts65Dn mice, a model of DS. In this study we have assessed the long-lasting effects of α5IA on in vivo LTP and behaviour in Ts65Dn mice. EXPERIMENTAL APPROACH: We made in vivo LTP recordings for six consecutive days in freely moving Ts65Dn mice and their wild-type littermates, treated with vehicle or α5IA. In parallel, Ts65Dn mice were assessed by various learning and memory tests (Y maze, Morris water maze, or the novel object recognition) for up to 7 days, following one single injection of α5IA or vehicle. KEY RESULTS: LTP was not evoked in vivo in Ts65Dn mice at hippocampal CA3-CA1 synapses. However, this deficit was sustainably reversed for at least six consecutive days following a single injection of α5IA. This long-lasting effect of α5IA was also observed when assessing working and long-term memory deficits in Ts65Dn mice. CONCLUSION AND IMPLICATIONS: We show for the first time in vivo LTP deficits in Ts65Dn mice. These deficits were restored for at least 6 days following acute treatment with α5IA and might be the substrate for the long-lasting pharmacological effects of α5IA on spatial working and long-term recognition and spatial memory tasks. Our results demonstrate the relevance of negative allosteric modulators of α5-containing GABAA receptors to the treatment of cognitive deficits associated with DS.


Assuntos
Disfunção Cognitiva , Síndrome de Down , Agonistas de Receptores de GABA-A/farmacologia , Potenciação de Longa Duração , Animais , Cognição , Modelos Animais de Doenças , Síndrome de Down/tratamento farmacológico , Aprendizagem em Labirinto , Camundongos , Receptores de GABA-A , Ácido gama-Aminobutírico
12.
Sci Rep ; 10(1): 1143, 2020 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-31980673

RESUMO

Neurodegenerative diseases, including Alzheimer's and Parkinson's disease, are characterized by increased protein aggregation in the brain, progressive neuronal loss, increased inflammation, and neurogenesis impairment. We analyzed the effects of a new purine derivative drug, PDD005, in attenuating mechanisms involved in the pathogenesis of neurodegenerative diseases, using both in vivo and in vitro models. We show that PDD005 is distributed to the brain and can rescue cognitive deficits associated with aging in mice. Treatment with PDD005 prevents impairment of neurogenesis by increasing sex-determining region Y-box 2, nestin, and also enhances synaptic function through upregulation of synaptophysin and postsynaptic density protein 95. PDD005 treatment also reduced neuro-inflammation by decreasing interleukin-1ß expression, activation of astrocytes, and microglia. We identified prohibitin as a potential target in mediating the therapeutic effects of PDD005 for the treatment of cognitive deficit in aging mice. Additionally, in the current study, glycogen synthase kinase appears to attenuate tau pathology.


Assuntos
Transtornos Cognitivos/prevenção & controle , Hipocampo/efeitos dos fármacos , Terapia de Alvo Molecular , Proteínas do Tecido Nervoso/antagonistas & inibidores , Fármacos Neuroprotetores/farmacologia , Proteínas Repressoras/antagonistas & inibidores , Tauopatias/prevenção & controle , Envelhecimento/psicologia , Animais , Barreira Hematoencefálica , Encéfalo/metabolismo , Células Cultivadas , Transtornos Cognitivos/tratamento farmacológico , Donepezila/farmacologia , Avaliação Pré-Clínica de Medicamentos , Células Endoteliais/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/biossíntese , Glicogênio Sintase Quinase 3 beta/genética , Interleucina-1beta/biossíntese , Interleucina-1beta/genética , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mitocôndrias/efeitos dos fármacos , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Neurogênese/efeitos dos fármacos , Neuroglia/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Fármacos Neuroprotetores/farmacocinética , Fosforilação/efeitos dos fármacos , Proibitinas , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Proteínas Repressoras/biossíntese , Proteínas Repressoras/genética , Tauopatias/tratamento farmacológico , Proteínas tau/metabolismo
14.
Genetics ; 180(1): 51-9, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18757940

RESUMO

Loss or gain of whole chromosomes, or parts of chromosomes, is found in various pathological conditions, such as cancer and aneuploidy, and results from the missegregation of chromosomes during cellular division or abnormal mitotic recombination. We introduce a novel strategy for determining the consequences of segmental aneuploid mosaicism, called targeted asymmetric sister chromatin event of recombination (TASCER). We took advantage of the Cre/loxP system, used extensively in embryonic stem cells for generating deletions and duplications of regions of interest, to induce recombination during the G2 phase. Using two loxP sites in a Cis configuration, we generated in vivo cells harboring microdeletions and microduplications for regions of interest covering up to 2.2 Mb. Using this approach in the mouse provides insight into the consequences of segmental aneuploidy for homologous regions of the human chromosome 21 on cell survival. Furthermore, TASCER shows that Cre-induced recombination is more efficient after DNA replication in vivo and provides an opportunity to evaluate, through genetic mosaics, the outcome of copy number variation and segmental aneuploidy in the mouse.


Assuntos
Mosaicismo , Recombinação Genética , Troca de Cromátide Irmã , Aneuploidia , Animais , Sobrevivência Celular , Mapeamento Cromossômico , Técnicas Genéticas , Genótipo , Hibridização in Situ Fluorescente , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mitose
15.
PLoS Genet ; 2(7): e86, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16839184

RESUMO

One of the challenges of genomic research after the completion of the human genome project is to assign a function to all the genes and to understand their interactions and organizations. Among the various techniques, the emergence of chromosome engineering tools with the aim to manipulate large genomic regions in the mouse model offers a powerful way to accelerate the discovery of gene functions and provides more mouse models to study normal and pathological developmental processes associated with aneuploidy. The combination of gene targeting in ES cells, recombinase technology, and other techniques makes it possible to generate new chromosomes carrying specific and defined deletions, duplications, inversions, and translocations that are accelerating functional analysis. This review presents the current status of chromosome engineering techniques and discusses the different applications as well as the implication of these new techniques in future research to better understand the function of chromosomal organization and structures.


Assuntos
Cromossomos/ultraestrutura , Embrião de Mamíferos/citologia , Genômica/métodos , Células-Tronco/citologia , Aneuploidia , Animais , Marcação de Genes , Engenharia Genética , Humanos , Camundongos , Modelos Genéticos , Recombinação Genética
16.
Sci Rep ; 9(1): 3914, 2019 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-30850713

RESUMO

Down syndrome is a common genetic disorder caused by trisomy of chromosome 21. Brain development in affected foetuses might be improved through prenatal treatment. One potential target is DYRK1A, a multifunctional kinase encoded by chromosome 21 that, when overexpressed, alters neuronal excitation-inhibition balance and increases GAD67 interneuron density. We used a green tea extract enriched in EGCG to inhibit DYRK1A function only during gestation of transgenic mice overexpressing Dyrk1a (mBACtgDyrk1a). Adult mice treated prenatally displayed reduced levels of inhibitory markers, restored VGAT1/VGLUT1 balance, and rescued density of GAD67 interneurons. Similar results for gabaergic and glutamatergic markers and interneuron density were obtained in Dp(16)1Yey mice, trisomic for 140 chromosome 21 orthologs; thus, prenatal EGCG exhibits efficacy in a more complex DS model. Finally, cognitive and behaviour testing showed that adult Dp(16)1Yey mice treated prenatally had improved novel object recognition memory but do not show improvement with Y maze paradigm. These findings provide empirical support for a prenatal intervention that targets specific neural circuitries.


Assuntos
Catequina/análogos & derivados , Síndrome de Down/dietoterapia , Glutamato Descarboxilase/fisiologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Chá , Animais , Encéfalo/embriologia , Encéfalo/crescimento & desenvolvimento , Encéfalo/fisiopatologia , Catequina/administração & dosagem , Cognição , Modelos Animais de Doenças , Síndrome de Down/fisiopatologia , Síndrome de Down/psicologia , Feminino , Interneurônios/patologia , Troca Materno-Fetal , Aprendizagem em Labirinto , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Gravidez , Proteínas Serina-Treonina Quinases/genética , Proteínas Tirosina Quinases/genética , Quinases Dyrk
17.
Nat Commun ; 10(1): 2129, 2019 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-31086189

RESUMO

De novo heterozygous missense variants in the γ-tubulin gene TUBG1 have been linked to human malformations of cortical development associated with intellectual disability and epilepsy. Here, we investigated through in-utero electroporation and in-vivo studies, how four of these variants affect cortical development. We show that TUBG1 mutants affect neuronal positioning, disrupting the locomotion of new-born neurons but without affecting progenitors' proliferation. We further demonstrate that pathogenic TUBG1 variants are linked to reduced microtubule dynamics but without major structural nor functional centrosome defects in subject-derived fibroblasts. Additionally, we developed a knock-in Tubg1Y92C/+ mouse model and assessed consequences of the mutation. Although centrosomal positioning in bipolar neurons is correct, they fail to initiate locomotion. Furthermore, Tubg1Y92C/+ animals show neuroanatomical and behavioral defects and increased epileptic cortical activity. We show that Tubg1Y92C/+ mice partially mimic the human phenotype and therefore represent a relevant model for further investigations of the physiopathology of cortical malformations.


Assuntos
Malformações do Desenvolvimento Cortical/genética , Microtúbulos/metabolismo , Neurogênese/genética , Neurônios/fisiologia , Tubulina (Proteína)/genética , Animais , Comportamento Animal , Movimento Celular/genética , Centrossomo/metabolismo , Córtex Cerebral/anormalidades , Córtex Cerebral/citologia , Córtex Cerebral/diagnóstico por imagem , Modelos Animais de Doenças , Embrião de Mamíferos , Epilepsia/genética , Feminino , Fibroblastos/citologia , Fibroblastos/metabolismo , Fibroblastos/ultraestrutura , Técnicas de Introdução de Genes , Predisposição Genética para Doença , Células HeLa , Humanos , Microscopia Intravital , Masculino , Camundongos , Camundongos Transgênicos , Microscopia Confocal , Microscopia Eletrônica , Microtúbulos/genética , Mutação de Sentido Incorreto
18.
Dis Model Mech ; 11(9)2018 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-30115750

RESUMO

Growing evidence supports the implication of DYRK1A in the development of cognitive deficits seen in Down syndrome (DS) and Alzheimer's disease (AD). We here demonstrate that pharmacological inhibition of brain DYRK1A is able to correct recognition memory deficits in three DS mouse models with increasing genetic complexity [Tg(Dyrk1a), Ts65Dn, Dp1Yey], all expressing an extra copy of Dyrk1a Overexpressed DYRK1A accumulates in the cytoplasm and at the synapse. Treatment of the three DS models with the pharmacological DYRK1A inhibitor leucettine L41 leads to normalization of DYRK1A activity and corrects the novel object cognitive impairment observed in these models. Brain functional magnetic resonance imaging reveals that this cognitive improvement is paralleled by functional connectivity remodelling of core brain areas involved in learning/memory processes. The impact of Dyrk1a trisomy and L41 treatment on brain phosphoproteins was investigated by a quantitative phosphoproteomics method, revealing the implication of synaptic (synapsin 1) and cytoskeletal components involved in synaptic response and axonal organization. These results encourage the development of DYRK1A inhibitors as drug candidates to treat cognitive deficits associated with DS and AD.


Assuntos
Disfunção Cognitiva/complicações , Disfunção Cognitiva/tratamento farmacológico , Dioxóis/farmacologia , Dioxóis/uso terapêutico , Síndrome de Down/complicações , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Sequência de Aminoácidos , Animais , Biocatálise , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Encéfalo/fisiopatologia , Disfunção Cognitiva/patologia , Citoplasma/metabolismo , Citoesqueleto/efeitos dos fármacos , Citoesqueleto/metabolismo , Dioxóis/química , Modelos Animais de Doenças , Síndrome de Down/patologia , Imidazóis/química , Imageamento por Ressonância Magnética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/fisiopatologia , Fosforilação , Ligação Proteica/efeitos dos fármacos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Proteômica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Sinapsinas/química , Sinapsinas/metabolismo , Quinases Dyrk
19.
Front Behav Neurosci ; 10: 104, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27375444

RESUMO

Down syndrome (DS) is one of the leading causes of intellectual disability, and patients with DS face various health issues, including learning and memory deficits, congenital heart disease, Alzheimer's disease (AD), leukemia, and cancer, leading to huge medical and social costs. Remarkable advances on DS research have been made in improving cognitive function in mouse models for future therapeutic approaches in patients. Among the different approaches, DYRK1A inhibitors have emerged as promising therapeutics to reduce DS cognitive deficits. DYRK1A is a dual-specificity kinase that is overexpressed in DS and plays a key role in neurogenesis, outgrowth of axons and dendrites, neuronal trafficking and aging. Its pivotal role in the DS phenotype makes it a prime target for the development of therapeutics. Recently, disruption of DYRK1A has been found in Autosomal Dominant Mental Retardation 7 (MRD7), resulting in severe mental deficiency. Recent advances in the development of kinase inhibitors are expected, in the near future, to remove DS from the list of incurable diseases, providing certain conditions such as drug dosage and correct timing for the optimum long-term treatment. In addition the exact molecular and cellular mechanisms that are targeted by the inhibition of DYRK1A are still to be discovered.

20.
PLoS One ; 10(2): e0115302, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25706610

RESUMO

Down syndrome (DS) results from one extra copy of human chromosome 21 and leads to several alterations including intellectual disabilities and locomotor defects. The transchromosomic Tc1 mouse model carrying an extra freely-segregating copy of human chromosome 21 was developed to better characterize the relation between genotype and phenotype in DS. The Tc1 mouse exhibits several locomotor and cognitive deficits related to DS. In this report we analyzed the contribution of the genetic dosage of 13 conserved mouse genes located between Abcg1 and U2af1, in the telomeric part of Hsa21. We used the Ms2Yah model carrying a deletion of the corresponding interval in the mouse genome to rescue gene dosage in the Tc1/Ms2Yah compound mice to determine how the different behavioral phenotypes are affected. We detected subtle changes with the Tc1/Ms2Yah mice performing better than the Tc1 individuals in the reversal paradigm of the Morris water maze. We also found that Tc1/Ms2Yah compound mutants performed better in the rotarod than the Tc1 mice. This data support the impact of genes from the Abcg1-U2af1 region as modifiers of Tc1-dependent memory and locomotor phenotypes. Our results emphasize the complex interactions between triplicated genes inducing DS features.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Transtornos Cognitivos/genética , Síndrome de Down/genética , Transtornos Neurológicos da Marcha/genética , Lipoproteínas/genética , Atividade Motora/genética , Proteínas Nucleares/genética , Ribonucleoproteínas/genética , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Animais , Cromossomos de Mamíferos , Cognição/fisiologia , Modelos Animais de Doenças , Dosagem de Genes , Genótipo , Aprendizagem em Labirinto/fisiologia , Camundongos , Fenótipo , Reversão de Aprendizagem/fisiologia , Teste de Desempenho do Rota-Rod , Fator de Processamento U2AF , Telômero
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