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1.
Front Psychiatry ; 13: 924956, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36405918

RESUMO

16p13.11 copy number variants (CNVs) have been associated with autism, schizophrenia, psychosis, intellectual disability, and epilepsy. The majority of 16p13.11 deletions or duplications occur within three well-defined intervals, and despite growing knowledge of the functions of individual genes within these intervals, the molecular mechanisms that underlie commonly observed clinical phenotypes remain largely unknown. Patient-derived, induced pluripotent stem cells (iPSCs) provide a platform for investigating the morphological, electrophysiological, and gene-expression changes that result from 16p13.11 CNVs in human-derived neurons. Patient derived iPSCs with varying sizes of 16p13.11 deletions and familial controls were differentiated into cortical neurons for phenotypic analysis. High-content imaging and morphological analysis of patient-derived neurons demonstrated an increase in neurite branching in patients compared with controls. Whole-transcriptome sequencing revealed expression level changes in neuron development and synaptic-related gene families, suggesting a defect in synapse formation. Subsequent quantification of synapse number demonstrated increased numbers of synapses on neurons derived from early-onset patients compared to controls. The identification of common phenotypes among neurons derived from patients with overlapping 16p13.11 deletions will further assist in ascertaining common pathways and targets that could be utilized for screening drug candidates. These studies can help to improve future treatment options and clinical outcomes for 16p13.11 deletion patients.

2.
Mol Ther ; 30(7): 2416-2428, 2022 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-35585789

RESUMO

We are in an emerging era of gene-based therapeutics with significant promise for rare genetic disorders. The potential is particularly significant for genetic central nervous system disorders that have begun to achieve Food and Drug Administration approval for select patient populations. This review summarizes the discussions and presentations of the National Institute of Mental Health-sponsored workshop "Gene-Based Therapeutics for Rare Genetic Neurodevelopmental Psychiatric Disorders," which was held in January 2021. Here, we distill the points raised regarding various precision medicine approaches related to neurodevelopmental and psychiatric disorders that may be amenable to gene-based therapies.


Assuntos
Transtornos Mentais , Medicina de Precisão , Humanos , Transtornos Mentais/genética , Transtornos Mentais/psicologia , Transtornos Mentais/terapia , Doenças Raras , Estados Unidos , United States Food and Drug Administration
3.
Arterioscler Thromb Vasc Biol ; 42(1): e27-e43, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34670408

RESUMO

OBJECTIVE: Capillary malformation (CM) occurs sporadically and is associated with Sturge-Weber syndrome. The somatic mosaic mutation in GNAQ (c.548G>A, p.R183Q) is enriched in endothelial cells (ECs) in skin CM and Sturge-Weber syndrome brain CM. Our goal was to investigate how the mutant Gαq (G-protein αq subunit) alters EC signaling and disrupts capillary morphogenesis. Approach and Results: We used lentiviral constructs to express p.R183Q or wild-type GNAQ in normal human endothelial colony forming cells (EC-R183Q and EC-WT, respectively). EC-R183Q constitutively activated PLC (phospholipase C) ß3, a downstream effector of Gαq. Activated PLCß3 was also detected in human CM tissue sections. Bulk RNA sequencing analyses of mutant versus wild-type EC indicated constitutive activation of PKC (protein kinase C), NF-κB (nuclear factor kappa B) and calcineurin signaling in EC-R183Q. Increased expression of downstream targets in these pathways, ANGPT2 (angiopoietin-2) and DSCR (Down syndrome critical region protein) 1.4 were confirmed by quantitative PCR and immunostaining of human CM tissue sections. The Gαq inhibitor YM-254890 as well as siRNA targeted to PLCß3 reduced mRNA expression levels of these targets in EC-R183Q while the pan-PKC inhibitor AEB071 reduced ANGPT2 but not DSCR1.4. EC-R183Q formed enlarged blood vessels in mice, reminiscent of those found in human CM. shRNA knockdown of ANGPT2 in EC-R183Q normalized the enlarged vessels to sizes comparable those formed by EC-WT. CONCLUSIONS: Gαq-R183Q, when expressed in ECs, establishes constitutively active PLCß3 signaling that leads to increased ANGPT2 and a proangiogenic, proinflammatory phenotype. EC-R183Q are sufficient to form enlarged CM-like vessels in mice, and suppression of ANGPT2 prevents the enlargement. Our study provides the first evidence that endothelial Gαq-R183Q is causative for CM and identifies ANGPT2 as a contributor to CM vascular phenotype.


Assuntos
Angiopoietina-2/metabolismo , Capilares/metabolismo , Células Progenitoras Endoteliais/metabolismo , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , Neovascularização Patológica , Síndrome de Sturge-Weber/metabolismo , Adolescente , Adulto , Idoso , Angiopoietina-2/genética , Animais , Capilares/anormalidades , Células Cultivadas , Criança , Pré-Escolar , Células Progenitoras Endoteliais/patologia , Células Progenitoras Endoteliais/transplante , Feminino , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/genética , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Lactente , Recém-Nascido , Masculino , Camundongos Nus , Mutação , Fenótipo , Fosfolipase C beta/genética , Fosfolipase C beta/metabolismo , Proteína Quinase C/metabolismo , Transdução de Sinais , Síndrome de Sturge-Weber/genética , Síndrome de Sturge-Weber/patologia , Regulação para Cima
4.
Cell Stem Cell ; 28(9): 1507-1515, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34478628

RESUMO

Over the course of the last decade, the biopharmaceutical industry has slowly adopted human inducible pluripotent stem cell (hiPSC) technology to enable the development of humanized model systems to test new therapeutic molecules and drug modalities. The adoption of hiPSC-based models by the industry has increased appreciably in the past 3-5 years. This increase has paralleled the explosion in availability of high-quality human genetic data to mine for new drug targets and the emergence of human-specific therapeutic modalities.


Assuntos
Células-Tronco Pluripotentes Induzidas , Células-Tronco Pluripotentes , Descoberta de Drogas , Humanos , Modelos Biológicos , Miócitos Cardíacos
5.
Cell Rep ; 31(12): 107780, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32579942

RESUMO

Tuberous sclerosis complex (TSC) is a neurogenetic disorder that leads to elevated mechanistic targeting of rapamycin complex 1 (mTORC1) activity. Cilia can be affected by mTORC1 signaling, and ciliary deficits are associated with neurodevelopmental disorders. Here, we examine whether neuronal cilia are affected in TSC. We show that cortical tubers from TSC patients and mutant mouse brains have fewer cilia. Using high-content image-based assays, we demonstrate that mTORC1 activity inversely correlates with ciliation in TSC1/2-deficient neurons. To investigate the mechanistic relationship between mTORC1 and cilia, we perform a phenotypic screen for mTORC1 inhibitors with TSC1/2-deficient neurons. We identify inhibitors of the heat shock protein 90 (Hsp90) that suppress mTORC1 through regulation of phosphatidylinositol 3-kinase (PI3K)/Akt signaling. Pharmacological inhibition of Hsp90 rescues ciliation through downregulation of Hsp27. Our study uncovers the heat-shock machinery as a druggable signaling node to restore mTORC1 activity and cilia due to loss of TSC1/2, and it provides broadly applicable platforms for studying TSC-related neuronal dysfunction.


Assuntos
Cílios/metabolismo , Resposta ao Choque Térmico , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Neurônios/metabolismo , Proteína 1 do Complexo Esclerose Tuberosa/metabolismo , Proteína 2 do Complexo Esclerose Tuberosa/metabolismo , Envelhecimento/metabolismo , Animais , Benzoquinonas/farmacologia , Encéfalo/patologia , Regulação para Baixo/efeitos dos fármacos , Proteínas de Choque Térmico HSP27/metabolismo , Proteínas de Choque Térmico HSP90/metabolismo , Resposta ao Choque Térmico/efeitos dos fármacos , Humanos , Lactamas Macrocíclicas/farmacologia , Camundongos Knockout , Neurônios/efeitos dos fármacos , Fenótipo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Sirolimo/farmacologia , Fatores de Tempo , Regulação para Cima/efeitos dos fármacos
6.
Mol Biol Cell ; 30(22): 2741-2743, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31609671

RESUMO

Discovery and development of new medicines requires the talent and passion of both academic and industrial scientists. Identifying the optimal set of circumstances for direct collaboration between academic and industry teams requires a mutual understanding of what each partner brings to the relationship, and an appreciation of the specialized capabilities and scope of work to be undertaken by each group. We provide our perspective on the who, what, where, why, and how for establishing therapeutic and translational research collaborations between academic and industry scientists.


Assuntos
Desenvolvimento de Medicamentos/métodos , Desenvolvimento de Medicamentos/tendências , Academias e Institutos/tendências , Comportamento Cooperativo , Indústria Farmacêutica/tendências , Humanos , Pesquisa Translacional Biomédica/tendências
7.
Cell Rep ; 28(12): 3224-3237.e5, 2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31533043

RESUMO

Dysregulated axonal trafficking of mitochondria is linked to neurodegenerative disorders. We report a high-content screen for small-molecule regulators of the axonal transport of mitochondria. Six compounds enhanced mitochondrial transport in the sub-micromolar range, acting via three cellular targets: F-actin, Tripeptidyl peptidase 1 (TPP1), or Aurora Kinase B (AurKB). Pharmacological inhibition or small hairpin RNA (shRNA) knockdown of each target promotes mitochondrial axonal transport in rat hippocampal neurons and induced pluripotent stem cell (iPSC)-derived human cortical neurons and enhances mitochondrial transport in iPSC-derived motor neurons from an amyotrophic lateral sclerosis (ALS) patient bearing one copy of SOD1A4V mutation. Our work identifies druggable regulators of axonal transport of mitochondria, provides broadly applicable methods for similar image-based screens, and suggests that restoration of proper axonal trafficking of mitochondria can be achieved in human ALS neurons.


Assuntos
Aminopeptidases/metabolismo , Esclerose Lateral Amiotrófica/metabolismo , Aurora Quinase B/metabolismo , Axônios/metabolismo , Dipeptidil Peptidases e Tripeptidil Peptidases/metabolismo , Hipocampo/metabolismo , Mitocôndrias/metabolismo , Serina Proteases/metabolismo , Aminopeptidases/genética , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/patologia , Animais , Aurora Quinase B/genética , Axônios/patologia , Transporte Biológico Ativo , Dipeptidil Peptidases e Tripeptidil Peptidases/genética , Feminino , Células HEK293 , Hipocampo/patologia , Humanos , Camundongos , Camundongos Knockout , Mitocôndrias/genética , Mitocôndrias/patologia , Ratos , Ratos Sprague-Dawley , Serina Proteases/genética , Superóxido Dismutase-1/genética , Superóxido Dismutase-1/metabolismo , Tripeptidil-Peptidase 1
8.
Transl Psychiatry ; 9(1): 151, 2019 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-31123247

RESUMO

Psychiatric disorders such as schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD) arise from complex interactions between genetic and environmental factors. Common genetic variants associated with multiple psychiatric disorders suggest that shared genetic architecture could contribute to divergent clinical syndromes. To evaluate shared transcriptional alterations across connected brain regions, Affymetrix microarrays were used to profile postmortem dorsolateral prefrontal cortex (DLPFC), hippocampus, and associative striatum from 19 well-matched tetrads of subjects with SCZ, BD, MDD, or unaffected controls. SCZ subjects showed a substantial burden of differentially expressed genes across all examined brain regions with the greatest effects in hippocampus, whereas BD and MDD showed less robust alterations. Pathway analysis of transcriptional profiles compared across diagnoses demonstrated commonly enriched pathways between all three disorders in hippocampus, significant overlap between SCZ and BD in DLPFC, but no significant overlap of enriched pathways between disorders in striatum. SCZ samples showed increased expression of transcripts associated with inflammation across all brain regions examined, which was not evident in BD or MDD, or in rat brain following chronic dosing with antipsychotic drugs. Several markers of inflammation were confirmed by RT-PCR in hippocampus, including S100A8/9, IL-6, MAFF, APOLD1, IFITM3, and BAG3. A cytokine ELISA panel showed significant increases in IL-2 and IL-12p70 protein content in hippocampal tissue collected from same SCZ subjects when compared to matched control subjects. These data suggest an overlapping subset of dysregulated pathways across psychiatric disorders; however, a widespread increase in inflammation appears to be a specific feature of the SCZ brain and is not likely to be attributable to chronic antipsychotic drug treatment.


Assuntos
Transtorno Bipolar , Corpo Estriado , Transtorno Depressivo Maior , Perfilação da Expressão Gênica , Hipocampo , Inflamação , Córtex Pré-Frontal , Esquizofrenia , Animais , Autopsia , Transtorno Bipolar/genética , Transtorno Bipolar/imunologia , Transtorno Bipolar/metabolismo , Corpo Estriado/imunologia , Corpo Estriado/metabolismo , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/imunologia , Transtorno Depressivo Maior/metabolismo , Hipocampo/imunologia , Hipocampo/metabolismo , Humanos , Inflamação/genética , Inflamação/imunologia , Inflamação/metabolismo , Masculino , Córtex Pré-Frontal/imunologia , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Sprague-Dawley , Esquizofrenia/genética , Esquizofrenia/imunologia , Esquizofrenia/metabolismo
9.
Neuron ; 100(4): 783-797, 2018 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-30465765

RESUMO

From the beginning, induced pluripotent stem cell (iPSC) technology was touted as a path to improve our understanding of disease biology and enable drug discovery. Advances in iPSC culture, genome engineering, and differentiation protocols have rapidly expanded the use of iPSC-derived disease models from the specialized work of stem cell biology into the mainstream toolkit of cellular neuroscience. Here we provide guidance for using iPSC-derived neurons for disease modeling with a focus on enabling screening platforms amenable to therapeutic drug discovery. We also highlight the potential for incorporating three-dimensional systems that may create more translational in vitro models.


Assuntos
Descoberta de Drogas/métodos , Células-Tronco Pluripotentes Induzidas/fisiologia , Doenças Neurodegenerativas/patologia , Neurônios/fisiologia , Pesquisa Translacional Biomédica/métodos , Animais , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Células Cultivadas , Técnicas de Cocultura , Descoberta de Drogas/tendências , Humanos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/genética , Neurônios/efeitos dos fármacos , Pesquisa Translacional Biomédica/tendências
10.
Mol Genet Metab Rep ; 16: 23-29, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29922587

RESUMO

Complex phenotypes may represent novel syndromes that are the composite interaction of several genetic and environmental factors. We describe an 9-year old male with high functioning autism spectrum disorder and Muckle-Wells syndrome who at age 5  years of age manifested perseverations that interfered with his functioning at home and at school. After age 6, he developed intermittent episodes of fatigue and somnolence lasting from hours to weeks that evolved over the course of months to more chronic hypersomnia. Whole exome sequencing showed three mutations in genes potentially involved in his clinical phenotype. The patient has a predicted pathogenic de novo heterozygous p.Ala681Thr mutation in the ATP1A3 gene (chr19:42480621C>T, GRCh37/hg19). Mutations in this gene are known to cause Alternating Hemiplegia of Childhood, Rapid Onset Dystonia Parkinsonism, and CAPOS syndrome, sometimes accompanied by autistic features. The patient also has compound heterozygosity for p.Arg490Lys/p.Val200Met mutations in the NLRP3 gene (chr1:247588214G>A and chr1:247587343G>A, respectively). NLRP3 mutations are associated in an autosomal dominant manner with clinically overlapping auto-inflammatory conditions including Muckle-Wells syndrome. The p.Arg490Lys is a known pathogenic mutation inherited from the patient's father. The p.Val200Met mutation, inherited from his mother, is a variant of unknown significance (VUS). Whether the de novoATP1A3mutation is responsible for or plays a role in the patient's episodes of fatigue and somnolence remains to be determined. The unprecedented combination of two NLRP3 mutations may be responsible for other aspects of his complex phenotype.

12.
J Med Chem ; 61(3): 1001-1018, 2018 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-29293004

RESUMO

Computational modeling was used to direct the synthesis of analogs of previously reported phosphodiesterase 2A (PDE2A) inhibitor 1 with an imidazotriazine core to yield compounds of significantly enhanced potency. The analog PF-05180999 (30) was subsequently identified as a preclinical candidate targeting cognitive impairment associated with schizophrenia. Compound 30 demonstrated potent binding to PDE2A in brain tissue, dose responsive mouse brain cGMP increases, and reversal of N-methyl-d-aspartate (NMDA) antagonist-induced (MK-801, ketamine) effects in electrophysiology and working memory models in rats. Preclinical pharmacokinetics revealed unbound brain/unbound plasma levels approaching unity and good oral bioavailability resulting in an average concentration at steady state (Cav,ss) predicted human dose of 30 mg once daily (q.d.). Modeling of a modified release formulation suggested that 25 mg twice daily (b.i.d.) could maintain plasma levels of 30 at or above targeted efficacious plasma levels for 24 h, which became part of the human clinical plan.


Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/antagonistas & inibidores , Descoberta de Drogas , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Animais , Disponibilidade Biológica , Encéfalo/fisiologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/química , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Humanos , Imidazóis/química , Imidazóis/metabolismo , Imidazóis/farmacocinética , Imidazóis/farmacologia , Concentração Inibidora 50 , Memória de Curto Prazo/efeitos dos fármacos , Simulação de Acoplamento Molecular , Conformação Proteica
13.
J Med Chem ; 60(13): 5673-5698, 2017 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-28574706

RESUMO

Phosphodiesterase 2A (PDE2A) inhibitors have been reported to demonstrate in vivo activity in preclinical models of cognition. To more fully explore the biology of PDE2A inhibition, we sought to identify potent PDE2A inhibitors with improved brain penetration as compared to current literature compounds. Applying estimated human dose calculations while simultaneously leveraging synthetically enabled chemistry and structure-based drug design has resulted in a highly potent, selective, brain penetrant compound 71 (PF-05085727) that effects in vivo biochemical changes commensurate with PDE2A inhibition along with behavioral and electrophysiological reversal of the effects of NMDA antagonists in rodents. This data supports the ability of PDE2A inhibitors to potentiate NMDA signaling and their further development for clinical cognition indications.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/antagonistas & inibidores , Desenho de Fármacos , Inibidores de Fosfodiesterase/química , Inibidores de Fosfodiesterase/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Cristalografia por Raios X , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/química , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/metabolismo , Cães , Haplorrinos , Humanos , Camundongos , Simulação de Acoplamento Molecular , Inibidores de Fosfodiesterase/administração & dosagem , Inibidores de Fosfodiesterase/farmacocinética , Ratos
14.
Dialogues Clin Neurosci ; 19(4): 335-343, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29398929

RESUMO

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by social deficits and repetitive/restrictive interests. ASD is associated with multiple comorbidities, including intellectual disability, anxiety, and epilepsy. Evidence that ASD is highly heritable has spurred major efforts to unravel its genetics, revealing possible contributions from hundreds of genes through rare and common variation and through copy-number changes. In this perspective, we provide an overview of the current state of ASD genetics and of how genetic research has spurred the development of in vivo and in vitro models using animals and patient cells to evaluate the impact of genetic mutations on cellular function leading to disease. Efforts to translate these findings into successful therapies have yet to bear fruit. We discuss how the valuable insight into the disorder provided by these new models can be used to better understand ASD and develop future clinical trials.


El trastorno del espectro autista (TEA) es un complejo trastorno del neurodesarrollo caracterizado por déficits sociales e intereses repetitivos/restrictivos. El TEA se asocia con múltiples comorbilidades, incluyendo discapacidad intelectual, ansiedad y epilepsia. La evidencia de la alta heredabilidad del TEA ha estimulado los mayores esfuerzos para descifrar su genética, revelando posibles contribuciones de cientos de genes a través de variaciones raras y comunes, y de la variabilidad en el número de copias. Desde esta perspectiva se entrega una panorámica del estado actual de la genética del TEA y de cómo la investigación genética ha estimulado el desarrollo de modelos in vivo e in vitro que emplean células de animales y de pacientes para evaluar el impacto de las mutaciones genéticas en la función celular que lleva a la enfermedad. Aún no han dado frutos los esfuerzos realizados en la traducción de estos hallazgos en terapias exitosas. Se discute cómo se puede emplear la valiosa información acerca del trastorno, proporcionada por estos nuevos modelos, para una mejor comprensión del TEA y para desarrollar futuros ensayos clínicos.


Le trouble du spectre de l'autisme (TSA) représente un trouble complexe neurodéveloppemental caractérisé par des déficits sociaux et des intérêts répétitifs et restreints. Les comorbidités associées au TSA sont multiples, comme la déficience intellectuelle, l'anxiété et l'épilepsie. La transmissibilité élevée démontrée du TSA a encouragé des efforts importants pour décoder sa génétique, des centaines de gènes étant potentiellement impliqués par des variations rares et courantes et par la variabilité du nombre de copies. Dans cette perspective, nous présentons un aperçu de l'état actuel de la génétique du TSA et de la façon dont la recherche génétique a stimulé le développement de modèles in vivo et in vitro utilisant des cellules humaines et animales pour évaluer l'incidence de mutations génétiques sur les fonctions cellulaires responsables de la maladie. Les efforts pour traduire ces résultats en traitements efficaces n'ont pas encore porté leurs fruits. Nous expliquons comment les informations précieuses apportées par ces nouveaux modèles peuvent être utilisées pour mieux comprendre le TSA et développer de futurs essais cliniques.


Assuntos
Transtorno Autístico/genética , Transtorno Autístico/terapia , Terapia Genética/métodos , Mutação , Pesquisa Translacional Biomédica , Animais , Modelos Animais de Doenças , Humanos
15.
J Neurosci ; 36(45): 11402-11410, 2016 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-27911742

RESUMO

Autism spectrum disorder (ASD) is a constellation of neurodevelopmental presentations with high heritability and both phenotypic and genetic heterogeneity. To date, mutations in hundreds of genes have been associated to varying degrees with increased ASD risk. A better understanding of the functions of these genes and whether they fit together in functional groups or impact similar neuronal circuits is needed to develop rational treatment strategies. We will review current areas of emphasis in ASD research, starting from human genetics and exploring how mouse models of human mutations have helped identify specific molecular pathways (protein synthesis and degradation, chromatin remodeling, intracellular signaling), which are linked to alterations in circuit function and cognitive/social behavior. We will conclude by discussing how we can leverage the findings on molecular and cellular alterations found in ASD to develop therapies for neurodevelopmental disorders.


Assuntos
Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/terapia , Encéfalo/metabolismo , Terapia Genética/métodos , Proteínas do Tecido Nervoso/genética , Transtorno do Espectro Autista/diagnóstico , Medicina Baseada em Evidências , Marcadores Genéticos/genética , Predisposição Genética para Doença/genética , Testes Genéticos/métodos , Humanos , Terapia de Alvo Molecular/métodos , Proteínas do Tecido Nervoso/metabolismo , Resultado do Tratamento
16.
Cold Spring Harb Mol Case Stud ; 2(5): a001008, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27626066

RESUMO

We describe a child with onset of command auditory hallucinations and behavioral regression at 6 yr of age in the context of longer standing selective mutism, aggression, and mild motor delays. His genetic evaluation included chromosomal microarray analysis and whole-exome sequencing. Sequencing revealed a previously unreported heterozygous de novo mutation c.385G>A in ATP1A3, predicted to result in a p.V129M amino acid change. This gene codes for a neuron-specific isoform of the catalytic α-subunit of the ATP-dependent transmembrane sodium-potassium pump. Heterozygous mutations in this gene have been reported as causing both sporadic and inherited forms of alternating hemiplegia of childhood and rapid-onset dystonia parkinsonism. We discuss the literature on phenotypes associated with known variants in ATP1A3, examine past functional studies of the role of ATP1A3 in neuronal function, and describe a novel clinical presentation associated with mutation of this gene.

17.
Biol Reprod ; 94(5): 110, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-27009040

RESUMO

The meiotic cell cycle of mammalian oocytes in preovulatory follicles is held in prophase arrest by diffusion of cGMP from the surrounding granulosa cells into the oocyte. Luteinizing hormone (LH) then releases meiotic arrest by lowering cGMP in the granulosa cells. The LH-induced reduction of cGMP is caused in part by a decrease in guanylyl cyclase activity, but the observation that the cGMP phosphodiesterase PDE5 is phosphorylated during LH signaling suggests that an increase in PDE5 activity could also contribute. To investigate this idea, we measured cGMP-hydrolytic activity in rat ovarian follicles. Basal activity was due primarily to PDE1A and PDE5, and LH increased PDE5 activity. The increase in PDE5 activity was accompanied by phosphorylation of PDE5 at serine 92, a protein kinase A/G consensus site. Both the phosphorylation and the increase in activity were promoted by elevating cAMP and opposed by inhibiting protein kinase A, supporting the hypothesis that LH activates PDE5 by stimulating its phosphorylation by protein kinase A. Inhibition of PDE5 activity partially suppressed LH-induced meiotic resumption as indicated by nuclear envelope breakdown, but inhibition of both PDE5 and PDE1 activities was needed to completely inhibit this response. These results show that activities of both PDE5 and PDE1 contribute to the LH-induced resumption of meiosis in rat oocytes, and that phosphorylation and activation of PDE5 is a regulatory mechanism.


Assuntos
GMP Cíclico/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 1/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/metabolismo , Hormônio Luteinizante/farmacologia , Meiose/efeitos dos fármacos , Folículo Ovariano/efeitos dos fármacos , Animais , Células Cultivadas , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Oócitos/efeitos dos fármacos , Oócitos/metabolismo , Folículo Ovariano/metabolismo , Fosforilação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
18.
Am J Med Genet A ; 170A(5): 1165-73, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26887912

RESUMO

Copy number variability at 16p13.11 has been associated with intellectual disability, autism, schizophrenia, epilepsy, and attention-deficit hyperactivity disorder. Adolescent/adult- onset psychosis has been reported in a subset of these cases. Here, we report on two children with CNVs in 16p13.11 that developed psychosis before the age of 7. The genotype and neuropsychiatric abnormalities of these patients highlight several overlapping genes that have possible mechanistic relevance to pathways previously implicated in Autism Spectrum Disorders, including the mTOR signaling and the ubiquitin-proteasome cascades. A careful screening of the 16p13.11 region is warranted in patients with childhood onset psychosis.


Assuntos
Transtorno Autístico/genética , Cromossomos Humanos Par 16/genética , Deficiências do Desenvolvimento/genética , Transtornos Psicóticos/genética , Esquizofrenia/genética , Transtorno Autístico/fisiopatologia , Criança , Pré-Escolar , Deleção Cromossômica , Hibridização Genômica Comparativa , Variações do Número de Cópias de DNA/genética , Deficiências do Desenvolvimento/fisiopatologia , Feminino , Estudos de Associação Genética , Humanos , Masculino , Transtornos Psicóticos/fisiopatologia , Esquizofrenia/fisiopatologia , Transdução de Sinais
19.
Sci Transl Med ; 8(320): 320ps1, 2016 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-26738793

RESUMO

The absence of mouse pharmacokinetic reference data hinders translation. An analysis of recent literature highlights a systematic lack of discussion regarding rationale for the selection of dosing paradigms in preclinical studies, and in particular for neuroscience studies in which the lack of brain penetration can limit target-organ exposure. We propose solutions to improve study design.


Assuntos
Avaliação Pré-Clínica de Medicamentos , Estatística como Assunto , Pesquisa Translacional Biomédica , Animais , Bases de Dados como Assunto , Humanos
20.
Neurobiol Dis ; 77: 220-7, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25796564

RESUMO

Brain-derived neurotrophic factor (BDNF) signaling is integral to a range of neural functions, including synaptic plasticity and exhibits activity-dependent regulation of expression. As altered BDNF signaling has been implicated in multiple psychiatric diseases, here we report a quantitative reverse transcription polymerase chain reaction (RT-PCR) analysis of mRNAs encoding TrkB, total BDNF, and the four most abundant BDNF transcripts (I, IIc, IV, and VI) in postmortem tissue from matched tetrads of subjects with schizophrenia, bipolar disorder, or major depressive disorder (MDD) and healthy comparison subjects. In all three regions examined, dorsolateral prefrontal cortex (DLPFC), associative striatum and hippocampus, total BDNF mRNA levels did not differ in any disease state. In DLPFC, BDNF IIc was significantly lower in schizophrenia relative to healthy comparison subjects. In hippocampus, BDNF I, IIc, and VI were lower in subjects with both schizophrenia and bipolar disorder relative to comparison subjects. In striatum, TrkB mRNA was lower in bipolar disorder and MDD, while BDNF IIc was elevated in MDD, relative to comparison subjects. These data highlight potential alterations in BDNF signaling in the corticohippocampal circuit in schizophrenia, and within the striatum in mood disorders. Novel therapies aimed at improving BDNF-TrkB signaling may therefore have potential to impact on a range of psychiatric disorders.


Assuntos
Transtorno Bipolar/patologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Encéfalo/metabolismo , Transtorno Depressivo Maior/patologia , Glicoproteínas de Membrana/metabolismo , Proteínas Tirosina Quinases/metabolismo , Esquizofrenia/patologia , Adulto , Fator Neurotrófico Derivado do Encéfalo/genética , Corpo Estriado/metabolismo , Feminino , Hipocampo/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Córtex Pré-Frontal/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptor trkB
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