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1.
Mol Psychiatry ; 26(3): 772-783, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-30976085

RESUMEN

The 3q29 deletion confers increased risk for neuropsychiatric phenotypes including intellectual disability, autism spectrum disorder, generalized anxiety disorder, and a >40-fold increased risk for schizophrenia. To investigate consequences of the 3q29 deletion in an experimental system, we used CRISPR/Cas9 technology to introduce a heterozygous deletion into the syntenic interval on C57BL/6 mouse chromosome 16. mRNA abundance for 20 of the 21 genes in the interval was reduced by ~50%, while protein levels were reduced for only a subset of these, suggesting a compensatory mechanism. Mice harboring the deletion manifested behavioral impairments in multiple domains including social interaction, cognitive function, acoustic startle, and amphetamine sensitivity, with some sex-dependent manifestations. In addition, 3q29 deletion mice showed reduced body weight throughout development consistent with the phenotype of 3q29 deletion syndrome patients. Of the genes within the interval, DLG1 has been hypothesized as a contributor to the neuropsychiatric phenotypes. However, we show that Dlg1+/- mice did not exhibit the behavioral deficits seen in mice harboring the full 3q29 deletion. These data demonstrate the following: the 3q29 deletion mice are a valuable experimental system that can be used to interrogate the biology of 3q29 deletion syndrome; behavioral manifestations of the 3q29 deletion may have sex-dependent effects; and mouse-specific behavior phenotypes associated with the 3q29 deletion are not solely due to haploinsufficiency of Dlg1.


Asunto(s)
Trastorno del Espectro Autista , Discapacidad Intelectual , Esquizofrenia , Animales , Niño , Deleción Cromosómica , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas , Discapacidades del Desarrollo/genética , Modelos Animales de Enfermedad , Humanos , Discapacidad Intelectual/genética , Ratones , Ratones Endogámicos C57BL , Fenotipo , Esquizofrenia/genética
2.
Annu Rev Pharmacol Toxicol ; 58: 429-449, 2018 01 06.
Artículo en Inglés | MEDLINE | ID: mdl-28968187

RESUMEN

The adhesion G protein-coupled receptors (aGPCRs) are an evolutionarily ancient family of receptors that play key roles in many different physiological processes. These receptors are notable for their exceptionally long ectodomains, which span several hundred to several thousand amino acids and contain various adhesion-related domains, as well as a GPCR autoproteolysis-inducing (GAIN) domain. The GAIN domain is conserved throughout almost the entire family and undergoes autoproteolysis to cleave the receptors into two noncovalently-associated protomers. Recent studies have revealed that the signaling activity of aGPCRs is largely determined by changes in the interactions among these protomers. We review recent advances in understanding aGPCR activation mechanisms and discuss the physiological roles and pharmacological properties of aGPCRs, with an eye toward the potential utility of these receptors as drug targets.


Asunto(s)
Receptores Acoplados a Proteínas G/metabolismo , Animales , Sistemas de Liberación de Medicamentos/métodos , Humanos , Unión Proteica/efectos de los fármacos , Transducción de Señal/efectos de los fármacos
3.
Hum Mutat ; 38(12): 1751-1760, 2017 12.
Artículo en Inglés | MEDLINE | ID: mdl-28891236

RESUMEN

Mutations in G protein-coupled receptors (GPCRs) that increase constitutive signaling activity can cause human disease. A de novo C-terminal mutation (R1465W) in the adhesion GPCR BAI2 (also known as ADGRB2) was identified in a patient suffering from progressive spastic paraparesis and other neurological symptoms. In vitro studies revealed that this mutation strongly increases the constitutive signaling activity of an N-terminally cleaved form of BAI2, which represents the activated form of the receptor. Further studies dissecting the mechanism(s) underling this effect revealed that wild-type BAI2 primarily couples to Gαz , with the R1465W mutation conferring increased coupling to Gαi . The R1465W mutation also increases the total and surface expression of BAI2. The mutation has no effect on receptor binding to ß-arrestins, but does perturb binding to the endocytic protein endophilin A1, identified here as a novel interacting partner for BAI2. These studies provide new insights into the signaling capabilities of the adhesion GPCR BAI2/ADGRB2 and shed light on how an apparent gain-of-function mutation to the receptor's C-terminus may lead to human disease.


Asunto(s)
Proteínas del Tejido Nervioso/genética , Receptores Acoplados a Proteínas G/genética , Transducción de Señal/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Sustitución de Aminoácidos , Línea Celular Tumoral , Femenino , Genes Reporteros , Humanos , Persona de Mediana Edad , Modelos Biológicos , Mutación , Proteínas del Tejido Nervioso/metabolismo , Unión Proteica , Transporte de Proteínas , Receptores Acoplados a Proteínas G/metabolismo , beta-Arrestinas/genética , beta-Arrestinas/metabolismo
4.
J Biol Chem ; 291(7): 3385-94, 2016 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-26710850

RESUMEN

The adhesion G protein-coupled receptors (aGPCRs) are a large yet poorly understood family of seven-transmembrane proteins. A defining characteristic of the aGPCR family is the conserved GAIN domain, which has autoproteolytic activity and can cleave the receptors near the first transmembrane domain. Several aGPCRs, including ADGRB1 (BAI1 or B1) and ADGRG1 (GPR56 or G1), have been found to exhibit significantly increased constitutive activity when truncated to mimic GAIN domain cleavage (ΔNT). Recent reports have suggested that the new N-terminal stalk, which is revealed by GAIN domain cleavage, can directly activate aGPCRs as a tethered agonist. We tested this hypothesis in studies on two distinct aGPCRs, B1 and G1, by engineering mutant receptors lacking the entire NT including the stalk (B1- and G1-SL, with "SL" indicating "stalkless"). These receptors were evaluated in a battery of signaling assays and compared with full-length wild-type and cleavage-mimicking (ΔNT) forms of the two receptors. We found that B1-SL, in multiple assays, exhibited robust signaling activity, suggesting that the membrane-proximal stalk region is not necessary for its activation. For G1, however, the results were mixed, with the SL mutant exhibiting robust activity in several signaling assays (including TGFα shedding, activation of NFAT luciferase, and ß-arrestin recruitment) but reduced activity relative to ΔNT in a distinct assay (activation of SRF luciferase). These data support a model in which the activation of certain pathways downstream of aGPCRs is stalk-dependent, whereas signaling to other pathways is stalk-independent.


Asunto(s)
Proteínas Angiogénicas/agonistas , Modelos Moleculares , Receptores Acoplados a Proteínas G/agonistas , Transducción de Señal , Regulación Alostérica , Sustitución de Aminoácidos , Proteínas Angiogénicas/química , Proteínas Angiogénicas/genética , Proteínas Angiogénicas/metabolismo , Arrestinas/química , Arrestinas/genética , Arrestinas/metabolismo , Secuencia Conservada , Genes Reporteros , Células HEK293 , Humanos , Ligandos , Factores de Transcripción NFATC/agonistas , Factores de Transcripción NFATC/química , Factores de Transcripción NFATC/genética , Factores de Transcripción NFATC/metabolismo , Fragmentos de Péptidos/agonistas , Fragmentos de Péptidos/química , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/metabolismo , Mutación Puntual , Conformación Proteica , Dominios y Motivos de Interacción de Proteínas , Proteolisis , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Proteínas Recombinantes de Fusión/química , Proteínas Recombinantes de Fusión/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Factor de Crecimiento Transformador alfa/química , Factor de Crecimiento Transformador alfa/genética , Factor de Crecimiento Transformador alfa/metabolismo , Ubiquitinación , beta-Arrestinas
5.
Am J Physiol Regul Integr Comp Physiol ; 305(9): R1076-84, 2013 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-24026073

RESUMEN

Maternal high-fat (HF) diet has long-term consequences on the metabolic phenotype of the offspring. Here, we determined the effects of postweaning exercise in offspring of rat dams fed HF diet during gestation and lactation. Pregnant Sprague-Dawley rats were maintained on chow or HF diet throughout gestation and lactation. All pups were weaned onto chow diet on postnatal day (PND) 21. At 4 wk of age, male pups were given free access to running wheels (RW) or remained sedentary (SED) for 3 wk, after which all rats remained sedentary, resulting in four groups: CHOW-SED, CHOW-RW, HF-SED, and HF-RW. Male HF offspring gained more body weight by PND7 compared with CHOW pups and maintained this weight difference through the entire experiment. Three weeks of postweaning exercise did not affect body weight gain in either CHOW or HF offspring, but reduced adiposity in HF offspring. Plasma leptin was decreased at the end of the 3-wk running period in HF-RW rats but was not different from HF-SED 9 wk after the exercise period ended. At 14 wk of age, intracerebroventricular injection of leptin suppressed food intake in CHOW-SED, CHOW-RW, and HF-RW, while it did not affect food intake in HF-SED group. At death, HF-RW rats also had higher leptin-induced phospho-STAT3 level in the arcuate nucleus than HF-SED rats. Both maternal HF diet and postweaning exercise had effects on hypothalamic neuropeptide and receptor mRNA expression in adult offspring. Our data suggest that postweaning exercise improves central leptin sensitivity and signaling in this model.


Asunto(s)
Fenómenos Fisiológicos Nutricionales de los Animales , Encéfalo/metabolismo , Dieta Alta en Grasa/efectos adversos , Lactancia/metabolismo , Leptina/sangre , Fenómenos Fisiologicos Nutricionales Maternos , Obesidad/prevención & control , Esfuerzo Físico , Efectos Tardíos de la Exposición Prenatal , Adiposidad , Animales , Glucemia/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/fisiopatología , Ingestión de Alimentos , Femenino , Regulación de la Expresión Génica , Prueba de Tolerancia a la Glucosa , Inyecciones Intraventriculares , Insulina/sangre , Leptina/administración & dosificación , Masculino , Neuropéptidos/genética , Neuropéptidos/metabolismo , Obesidad/etiología , Obesidad/metabolismo , Obesidad/fisiopatología , Fosforilación , Embarazo , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de Neuropéptido/genética , Receptores de Neuropéptido/metabolismo , Factor de Transcripción STAT3/metabolismo , Conducta Sedentaria , Transducción de Señal , Destete , Aumento de Peso
6.
Genome Med ; 15(1): 35, 2023 05 10.
Artículo en Inglés | MEDLINE | ID: mdl-37165454

RESUMEN

BACKGROUND: High sequence identity between segmental duplications (SDs) can facilitate copy number variants (CNVs) via non-allelic homologous recombination (NAHR). These CNVs are one of the fundamental causes of genomic disorders such as the 3q29 deletion syndrome (del3q29S). There are 21 protein-coding genes lost or gained as a result of such recurrent 1.6-Mbp deletions or duplications, respectively, in the 3q29 locus. While NAHR plays a role in CNV occurrence, the factors that increase the risk of NAHR at this particular locus are not well understood. METHODS: We employed an optical genome mapping technique to characterize the 3q29 locus in 161 unaffected individuals, 16 probands with del3q29S and their parents, and 2 probands with the 3q29 duplication syndrome (dup3q29S). Long-read sequencing-based haplotype resolved de novo assemblies from 44 unaffected individuals, and 1 trio was used for orthogonal validation of haplotypes and deletion breakpoints. RESULTS: In total, we discovered 34 haplotypes, of which 19 were novel haplotypes. Among these 19 novel haplotypes, 18 were detected in unaffected individuals, while 1 novel haplotype was detected on the parent-of-origin chromosome of a proband with the del3q29S. Phased assemblies from 44 unaffected individuals enabled the orthogonal validation of 20 haplotypes. In 89% (16/18) of the probands, breakpoints were confined to paralogous copies of a 20-kbp segment within the 3q29 SDs. In one del3q29S proband, the breakpoint was confined to a 374-bp region using long-read sequencing. Furthermore, we categorized del3q29S cases into three classes and dup3q29S cases into two classes based on breakpoints. Finally, we found no evidence of inversions in parent-of-origin chromosomes. CONCLUSIONS: We have generated the most comprehensive haplotype map for the 3q29 locus using unaffected individuals, probands with del3q29S or dup3q29S, and available parents, and also determined the deletion breakpoint to be within a 374-bp region in one proband with del3q29S. These results should provide a better understanding of the underlying genetic architecture that contributes to the etiology of del3q29S and dup3q29S.


Asunto(s)
Genómica , Duplicaciones Segmentarias en el Genoma , Humanos , Mapeo Cromosómico , Síndrome , Haplotipos , Variaciones en el Número de Copia de ADN
7.
Sci Adv ; 9(33): eadh0558, 2023 08 18.
Artículo en Inglés | MEDLINE | ID: mdl-37585521

RESUMEN

The 1.6-megabase deletion at chromosome 3q29 (3q29Del) is the strongest identified genetic risk factor for schizophrenia, but the effects of this variant on neurodevelopment are not well understood. We interrogated the developing neural transcriptome in two experimental model systems with complementary advantages: isogenic human cortical organoids and isocortex from the 3q29Del mouse model. We profiled transcriptomes from isogenic cortical organoids that were aged for 2 and 12 months, as well as perinatal mouse isocortex, all at single-cell resolution. Systematic pathway analysis implicated dysregulation of mitochondrial function and energy metabolism. These molecular signatures were supported by analysis of oxidative phosphorylation protein complex expression in mouse brain and assays of mitochondrial function in engineered cell lines, which revealed a lack of metabolic flexibility and a contribution of the 3q29 gene PAK2. Together, these data indicate that metabolic disruption is associated with 3q29Del and is conserved across species.


Asunto(s)
Discapacidad Intelectual , Neocórtex , Esquizofrenia , Niño , Humanos , Animales , Ratones , Anciano , Esquizofrenia/genética , Deleción Cromosómica , Discapacidades del Desarrollo/complicaciones , Discapacidades del Desarrollo/genética
8.
bioRxiv ; 2023 May 26.
Artículo en Inglés | MEDLINE | ID: mdl-36747819

RESUMEN

Recent advances in the genetics of schizophrenia (SCZ) have identified rare variants that confer high disease risk, including a 1.6 Mb deletion at chromosome 3q29 with a staggeringly large effect size (O.R. > 40). Understanding the impact of the 3q29 deletion (3q29Del) on the developing CNS may therefore lead to insights about the pathobiology of schizophrenia. To gain clues about the molecular and cellular perturbations caused by the 3q29 deletion, we interrogated transcriptomic effects in two experimental model systems with complementary advantages: isogenic human forebrain cortical organoids and isocortex from the 3q29Del mouse model. We first created isogenic lines by engineering the full 3q29Del into an induced pluripotent stem cell line from a neurotypical individual. We profiled transcriptomes from isogenic cortical organoids that were aged for 2 months and 12 months, as well as day p7 perinatal mouse isocortex, all at single cell resolution. Differential expression analysis by genotype in each cell-type cluster revealed that more than half of the differentially expressed genes identified in mouse cortex were also differentially expressed in human cortical organoids, and strong correlations were observed in mouse-human differential gene expression across most major cell-types. We systematically filtered differentially expressed genes to identify changes occurring in both model systems. Pathway analysis on this filtered gene set implicated dysregulation of mitochondrial function and energy metabolism, although the direction of the effect was dependent on developmental timepoint. Transcriptomic changes were validated at the protein level by analysis of oxidative phosphorylation protein complexes in mouse brain tissue. Assays of mitochondrial function in human heterologous cells further confirmed robust mitochondrial dysregulation in 3q29Del cells, and these effects are partially recapitulated by ablation of the 3q29Del gene PAK2 . Taken together these data indicate that metabolic disruption is associated with 3q29Del and is conserved across species. These results converge with data from other rare SCZ-associated variants as well as idiopathic schizophrenia, suggesting that mitochondrial dysfunction may be a significant but overlooked contributing factor to the development of psychotic disorders. This cross-species scRNA-seq analysis of the SCZ-associated 3q29 deletion reveals that this copy number variant may produce early and persistent changes in cellular metabolism that are relevant to human neurodevelopment.

9.
10.
J Dev Behav Pediatr ; 43(2): e94-e102, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-34320535

RESUMEN

OBJECTIVE: Genetic diagnoses are increasingly common in cases of intellectual disability and developmental delay. Although ascertainment of a relatively common, well-studied variant may provide guidance related to treatments and developmental expectations, it is less clear how the diagnosis of a rare variant affects caregivers, especially when the phenotype may include later-onset manifestations such as psychosis. In this study, we sought to identify caregiver concerns in the first qualitative study to assess the psychosocial impact of diagnosis on caregivers of individuals with 3q29 deletion syndrome (3q29Del), which is associated with a 40-fold increase in risk for psychosis. METHODS: Participants were recruited from the national 3q29Del registry housed at Emory University (3q29deletion.org). Fifteen participants completed a semistructured phone interview during which they were asked about their experiences before, during, and after their child received a diagnosis of 3q29Del. Interview responses were analyzed using the general inductive approach, and overarching themes were identified. RESULTS: We identified the following overarching themes: difficult "diagnostic odyssey," mixed feelings about diagnosis, frustration with degree of uncertainty, and importance of resources. Importantly, our data suggest that future risk for psychosis is often not disclosed by medical professionals, consistent with the experience of individuals with 22q11.2 deletion syndrome. CONCLUSIONS: These results highlight potential gaps in how caregivers are informed of risk for adult-onset conditions and indicate key caregiver concerns for consideration in the diagnosis of 3q29Del.


Asunto(s)
Discapacidad Intelectual , Trastornos Psicóticos , Cuidadores/psicología , Familia , Humanos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Investigación Cualitativa
11.
Exp Neurol ; 351: 113994, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35114205

RESUMEN

The adhesion G protein-coupled receptor BAI1/ADGRB1 plays an important role in suppressing angiogenesis, mediating phagocytosis, and acting as a brain tumor suppressor. BAI1 is also a critical regulator of dendritic spine and excitatory synapse development and interacts with several autism-relevant proteins. However, little is known about the relationship between altered BAI1 function and clinically relevant phenotypes. Therefore, we studied the effect of reduced expression of full length Bai1 on behavior, seizure susceptibility, and brain morphology in Adgrb1 mutant mice. We compared homozygous (Adgrb1-/-), heterozygous (Adgrb1+/-), and wild-type (WT) littermates using a battery of tests to assess social behavior, anxiety, repetitive behavior, locomotor function, and seizure susceptibility. We found that Adgrb1-/- mice showed significant social behavior deficits and increased vulnerability to seizures. Adgrb1-/- mice also showed delayed growth and reduced brain weight. Furthermore, reduced neuron density and increased apoptosis during brain development were observed in the hippocampus of Adgrb1-/- mice, while levels of astrogliosis and microgliosis were comparable to WT littermates. These results show that reduced levels of full length Bai1 is associated with a broader range of clinically relevant phenotypes than previously reported.


Asunto(s)
Proteínas Angiogénicas/metabolismo , Receptores Acoplados a Proteínas G , Proteínas Angiogénicas/genética , Animales , Encéfalo/metabolismo , Hipocampo/metabolismo , Ratones , Receptores Acoplados a Proteínas G/genética , Convulsiones/genética , Convulsiones/metabolismo
12.
Transl Psychiatry ; 12(1): 66, 2022 02 17.
Artículo en Inglés | MEDLINE | ID: mdl-35177588

RESUMEN

The 1.6 Mb 3q29 deletion is associated with developmental and psychiatric phenotypes, including a 40-fold increased risk for schizophrenia. Reduced birth weight and a high prevalence of feeding disorders in patients suggest underlying metabolic dysregulation. We investigated 3q29 deletion-induced metabolic changes using our previously generated heterozygous B6.Del16+/Bdh1-Tfrc mouse model. Animals were provided either standard chow (STD) or high-fat diet (HFD). Growth curves were performed on HFD mice to assess weight change (n = 30-50/group). Indirect calorimetry and untargeted metabolomics were performed on STD and HFD mice to evaluate metabolic phenotypes (n = 8-14/group). A behavioral battery was performed on STD and HFD mice to assess behavior change after the HFD challenge (n = 5-13/group). We found that B6.Del16+/Bdh1-Tfrc animals preferentially use dietary lipids as an energy source. Untargeted metabolomics of liver tissue showed a strong sex-dependent effect of the 3q29 deletion on fat metabolism. A HFD partially rescued the 3q29 deletion-associated weight deficit in females, but not males. Untargeted metabolomics of liver tissue after HFD revealed persistent fat metabolism alterations in females. The HFD did not affect B6.Del16+/Bdh1-Tfrc behavioral phenotypes, suggesting that 3q29 deletion-associated metabolic and behavioral outcomes are uncoupled. Our data suggest that dietary interventions to improve weight phenotypes in 3q29 deletion syndrome patients are unlikely to exacerbate behavioral manifestations. Our study also highlights the importance of assessing sex in metabolic studies and suggests that mechanisms underlying 3q29 deletion-associated metabolic phenotypes are sex-specific.


Asunto(s)
Discapacidad Intelectual , Esquizofrenia , Animales , Niño , Deleción Cromosómica , Discapacidades del Desarrollo/genética , Dieta Alta en Grasa , Femenino , Humanos , Discapacidad Intelectual/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Fenotipo , Esquizofrenia/complicaciones , Esquizofrenia/genética
13.
Transl Psychiatry ; 11(1): 357, 2021 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-34131099

RESUMEN

The 3q29 deletion (3q29Del) confers high risk for schizophrenia and other neurodevelopmental and psychiatric disorders. However, no single gene in this interval is definitively associated with disease, prompting the hypothesis that neuropsychiatric sequelae emerge upon loss of multiple functionally-connected genes. 3q29 genes are unevenly annotated and the impact of 3q29Del on the human neural transcriptome is unknown. To systematically formulate unbiased hypotheses about molecular mechanisms linking 3q29Del to neuropsychiatric illness, we conducted a systems-level network analysis of the non-pathological adult human cortical transcriptome and generated evidence-based predictions that relate 3q29 genes to novel functions and disease associations. The 21 protein-coding genes located in the interval segregated into seven clusters of highly co-expressed genes, demonstrating both convergent and distributed effects of 3q29Del across the interrogated transcriptomic landscape. Pathway analysis of these clusters indicated involvement in nervous-system functions, including synaptic signaling and organization, as well as core cellular functions, including transcriptional regulation, posttranslational modifications, chromatin remodeling, and mitochondrial metabolism. Top network-neighbors of 3q29 genes showed significant overlap with known schizophrenia, autism, and intellectual disability-risk genes, suggesting that 3q29Del biology is relevant to idiopathic disease. Leveraging "guilt by association", we propose nine 3q29 genes, including one hub gene, as prioritized drivers of neuropsychiatric risk. These results provide testable hypotheses for experimental analysis on causal drivers and mechanisms of the largest known genetic risk factor for schizophrenia and highlight the study of normal function in non-pathological postmortem tissue to further our understanding of psychiatric genetics, especially for rare syndromes like 3q29Del, where access to neural tissue from carriers is unavailable or limited.


Asunto(s)
Discapacidad Intelectual , Transcriptoma , Adulto , Niño , Deleción Cromosómica , Discapacidades del Desarrollo/genética , Humanos , Discapacidad Intelectual/genética , Fenotipo
14.
Ann N Y Acad Sci ; 1506(1): 5-17, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34342000

RESUMEN

Neurodevelopmental neuropsychiatric disorders, such as autism spectrum disorder and schizophrenia, have strong genetic risk components, but the underlying mechanisms have proven difficult to decipher. Rare, high-risk variants may offer an opportunity to delineate the biological mechanisms responsible more clearly for more common idiopathic diseases. Indeed, different rare variants can cause the same behavioral phenotype, demonstrating genetic heterogeneity, while the same rare variant can cause different behavioral phenotypes, demonstrating variable expressivity. These observations suggest convergent underlying biological and neurological mechanisms; identification of these mechanisms may ultimately reveal new therapeutic targets. At the 2021 Keystone eSymposium "Neuropsychiatric and Neurodevelopmental Disorders: Harnessing Rare Variants" a panel of experts in the field described significant progress in genomic discovery and human phenotyping and raised several consistent issues, including the need for detailed natural history studies of rare disorders, the challenges in cohort recruitment, and the importance of viewing phenotypes as quantitative traits that are impacted by rare variants.


Asunto(s)
Congresos como Asunto/tendencias , Variación Genética/genética , Trastornos Mentales/genética , Trastornos del Neurodesarrollo/genética , Penetrancia , Informe de Investigación , Humanos , Trastornos Mentales/diagnóstico , Trastornos Mentales/psicología , Trastornos del Neurodesarrollo/diagnóstico , Trastornos del Neurodesarrollo/psicología
15.
Neuron ; 107(2): 292-305.e6, 2020 07 22.
Artículo en Inglés | MEDLINE | ID: mdl-32375063

RESUMEN

GGGGCC hexanucleotide repeat expansions (HREs) in C9orf72 cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) and lead to the production of aggregating dipeptide repeat proteins (DPRs) via repeat associated non-AUG (RAN) translation. Here, we show the similar intronic GGCCTG HREs that causes spinocerebellar ataxia type 36 (SCA36) is also translated into DPRs, including poly(GP) and poly(PR). We demonstrate that poly(GP) is more abundant in SCA36 compared to c9ALS/FTD patient tissue due to canonical AUG-mediated translation from intron-retained GGCCTG repeat RNAs. However, the frequency of the antisense RAN translation product poly(PR) is comparable between c9ALS/FTD and SCA36 patient samples. Interestingly, in SCA36 patient tissue, poly(GP) exists as a soluble species, and no TDP-43 pathology is present. We show that aggregate-prone chimeric DPR (cDPR) species underlie the divergent DPR pathology between c9ALS/FTD and SCA36. These findings reveal key differences in translation, solubility, and protein aggregation of DPRs between c9ALS/FTD and SCA36.


Asunto(s)
Esclerosis Amiotrófica Lateral/genética , Proteína C9orf72/genética , Dipéptidos/genética , Demencia Frontotemporal/genética , Proteínas Mutantes Quiméricas/genética , Ataxias Espinocerebelosas/genética , Secuencia de Aminoácidos , Animales , Animales Recién Nacidos , Elementos sin Sentido (Genética)/genética , Expansión de las Repeticiones de ADN , Femenino , Humanos , Intrones/genética , Ratones , Ratones Endogámicos C57BL , Embarazo , Secuencias Repetitivas de Ácidos Nucleicos
16.
Neuron ; 86(2): 356-9, 2015 Apr 22.
Artículo en Inglés | MEDLINE | ID: mdl-25905809

RESUMEN

Internet brain training programs, where consumers serve as both subjects and funders of the research, represent the closest engagement many individuals have with neuroscience. Safeguards are needed to protect participants' privacy and the evolving scientific enterprise of big data.


Asunto(s)
Recolección de Datos/ética , Internet/ética , Aprendizaje Basado en Problemas/ética , Juegos de Video/ética , Investigación Conductal/ética , Investigación Conductal/métodos , Refuerzo Biomédico , Cognición/fisiología , Confidencialidad , Bases de Datos como Asunto/ética , Decepción , Humanos , Consentimiento Informado , Privacidad , Aprendizaje Basado en Problemas/legislación & jurisprudencia , Proyectos de Investigación , Transferencia de Experiencia en Psicología/ética , Estados Unidos
17.
Trends Pharmacol Sci ; 35(4): 208-15, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24642458

RESUMEN

The brain-specific angiogenesis inhibitors 1-3 (BAI1-3) comprise a subfamily of adhesion G-protein-coupled receptors (GPCRs). These receptors are highly expressed in the brain and were first studied for their ability to inhibit angiogenesis and tumor formation. Subsequently, BAI1 was found to play roles in apoptotic cell phagocytosis and myoblast fusion. Until recently, however, little was known about the physiological importance of the BAI subfamily in the context of normal brain function. Recent work has provided evidence for key roles of BAI1-3 in the regulation of synaptogenesis and dendritic spine formation. In this review, we summarize the current understanding of the BAI subfamily with regard to downstream signaling pathways, physiological actions, and potential importance as novel drug targets in the treatment of psychiatric and neurological diseases.


Asunto(s)
Proteínas Angiogénicas/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Sinapsis/metabolismo , Animales , Humanos
19.
Epigenetics ; 9(3): 437-47, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24365909

RESUMEN

There is ample evidence that exposure to stress during gestation increases the risk of the offspring to develop mood disorders. Brain-derived neurotrophic factor (Bdnf) plays a critical role during neuronal development and is therefore a prime candidate to modulate neuronal signaling in adult offspring of rat dams that were stressed during gestation. In the current study, we tested the hypothesis that alterations in Bdnf expression in prenatally stressed (PNS) offspring are mediated by changes in DNA methylation in exons IV and VI of the Bdnf gene. We observed decreased Bdnf expression in the amygdala and hippocampus of prenatally stressed rats both at weaning and in adulthood. This decrease in Bdnf expression was accompanied by increased DNA methylation in Bdnf exon IV in the amygdala and hippocampus, suggesting that PNS-induced reduction in Bdnf expression may, at least in part, be mediated by increased DNA methylation of Bdnf exon IV. Expression of DNA methyltransferases (Dnmt) 1 and 3a was increased in PNS rats in the amygdala and hippocampus. Our data suggest that PNS induces decreases in Bdnf expression that may at least in part be mediated by increased DNA methylation of Bdnf exon IV.


Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/genética , Metilación de ADN , Estrés Psicológico/genética , Amígdala del Cerebelo/embriología , Amígdala del Cerebelo/crecimiento & desarrollo , Amígdala del Cerebelo/metabolismo , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , ADN (Citosina-5-)-Metiltransferasa 1 , ADN (Citosina-5-)-Metiltransferasas/genética , ADN (Citosina-5-)-Metiltransferasas/metabolismo , ADN Metiltransferasa 3A , Exones , Femenino , Hipocampo/embriología , Hipocampo/crecimiento & desarrollo , Hipocampo/metabolismo , Masculino , Corteza Prefrontal/embriología , Corteza Prefrontal/crecimiento & desarrollo , Corteza Prefrontal/metabolismo , Embarazo , Efectos Tardíos de la Exposición Prenatal/genética , Efectos Tardíos de la Exposición Prenatal/metabolismo , Regiones Promotoras Genéticas , Ratas , Ratas Sprague-Dawley , Estrés Psicológico/metabolismo
20.
Psychopharmacology (Berl) ; 228(2): 263-70, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23494229

RESUMEN

RATIONALE: High doses of cocaine can elicit seizures in humans and in laboratory animals. Several mechanisms have been proposed for the induction of seizures by cocaine, including enhanced monoaminergic signaling, blockade of ion channels, and alterations in GABA and glutamate transmission. Mutations in the SCN1A gene, which encodes the central nervous system (CNS) voltage-gated sodium channel (VGSC) Nav1.1, are responsible for several human epilepsy disorders including Dravet syndrome and genetic (generalized) epilepsy with febrile seizures plus (GEFS+). Mice heterozygous for the R1648H GEFS+ mutation (RH mice) exhibit reduced interneuron excitability, spontaneous seizures, and lower thresholds to flurothyl- and hyperthermia-induced seizures. However, it is unknown whether impaired CNS VGSC function or a genetic predisposition to epilepsy increases susceptibility to cocaine-induced seizures. OBJECTIVES: Our primary goal was to determine whether Scn1a dysfunction caused by the RH mutation alters sensitivity to cocaine-induced behavioral and electrographic (EEG) seizures. We also tested novelty- and cocaine-induced locomotor activity and assessed the expression of Nav1.1 in midbrain dopaminergic neurons. RESULTS: We found that RH mice had a profound increase in cocaine-induced behavioral seizure susceptibility compared to wild-type (WT) controls, which was confirmed with cortical EEG recordings. By contrast, although the RH mice were hyperactive in novel environments, cocaine-induced locomotor activity was comparable between the mutants and WT littermates. Finally, immunofluorescence experiments revealed a lack of Nav1.1 immunoreactivity in dopaminergic neurons. CONCLUSION: These data indicate that a disease-causing CNS VGSC mutation confers susceptibility to the proconvulsant, but not motoric, effects of cocaine.


Asunto(s)
Cocaína/toxicidad , Epilepsia/genética , Canal de Sodio Activado por Voltaje NAV1.1/genética , Convulsiones/inducido químicamente , Animales , Cocaína/administración & dosificación , Dopamina/metabolismo , Relación Dosis-Respuesta a Droga , Electrocardiografía , Electroencefalografía , Técnica del Anticuerpo Fluorescente , Predisposición Genética a la Enfermedad , Masculino , Ratones , Actividad Motora/efectos de los fármacos , Mutación , Convulsiones/genética
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