Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 6 de 6
Filtrar
1.
Mol Psychiatry ; 28(4): 1747-1769, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36604605

RESUMEN

Copy number variations (CNVs) are associated with psychiatric and neurodevelopmental disorders (NDDs), and most, including the recurrent 15q13.3 microdeletion disorder, have unknown disease mechanisms. We used a heterozygous 15q13.3 microdeletion mouse model and patient iPSC-derived neurons to reveal developmental defects in neuronal maturation and network activity. To identify the underlying molecular dysfunction, we developed a neuron-specific proximity-labeling proteomics (BioID2) pipeline, combined with patient mutations, to target the 15q13.3 CNV genetic driver OTUD7A. OTUD7A is an emerging independent NDD risk gene with no known function in the brain, but has putative deubiquitinase function. The OTUD7A protein-protein interaction network included synaptic, axonal, and cytoskeletal proteins and was enriched for ASD and epilepsy risk genes (Ank3, Ank2, SPTAN1, SPTBN1). The interactions between OTUD7A and Ankyrin-G (Ank3) and Ankyrin-B (Ank2) were disrupted by an epilepsy-associated OTUD7A L233F variant. Further investigation of Ankyrin-G in mouse and human 15q13.3 microdeletion and OTUD7AL233F/L233F models revealed protein instability, increased polyubiquitination, and decreased levels in the axon initial segment, while structured illumination microscopy identified reduced Ankyrin-G nanodomains in dendritic spines. Functional analysis of human 15q13.3 microdeletion and OTUD7AL233F/L233F models revealed shared and distinct impairments to axonal growth and intrinsic excitability. Importantly, restoring OTUD7A or Ankyrin-G expression in 15q13.3 microdeletion neurons led to a reversal of abnormalities. These data reveal a critical OTUD7A-Ankyrin pathway in neuronal development, which is impaired in the 15q13.3 microdeletion syndrome, leading to neuronal dysfunction. Furthermore, our study highlights the utility of targeting CNV genes using cell type-specific proteomics to identify shared and unexplored disease mechanisms across NDDs.


Asunto(s)
Ancirinas , Epilepsia , Humanos , Ratones , Animales , Ancirinas/genética , Variaciones en el Número de Copia de ADN , Epilepsia/genética , Neuronas
2.
Am J Hum Genet ; 102(2): 278-295, 2018 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-29395074

RESUMEN

Copy-number variations (CNVs) are strong risk factors for neurodevelopmental and psychiatric disorders. The 15q13.3 microdeletion syndrome region contains up to ten genes and is associated with numerous conditions, including autism spectrum disorder (ASD), epilepsy, schizophrenia, and intellectual disability; however, the mechanisms underlying the pathogenesis of 15q13.3 microdeletion syndrome remain unknown. We combined whole-genome sequencing, human brain gene expression (proteome and transcriptome), and a mouse model with a syntenic heterozygous deletion (Df(h15q13)/+ mice) and determined that the microdeletion results in abnormal development of cortical dendritic spines and dendrite outgrowth. Analysis of large-scale genomic, transcriptomic, and proteomic data identified OTUD7A as a critical gene for brain function. OTUD7A was found to localize to dendritic and spine compartments in cortical neurons, and its reduced levels in Df(h15q13)/+ cortical neurons contributed to the dendritic spine and dendrite outgrowth deficits. Our results reveal OTUD7A as a major regulatory gene for 15q13.3 microdeletion syndrome phenotypes that contribute to the disease mechanism through abnormal cortical neuron morphological development.


Asunto(s)
Trastornos de los Cromosomas/enzimología , Trastornos de los Cromosomas/genética , Enzimas Desubicuitinizantes/fisiología , Endopeptidasas/genética , Discapacidad Intelectual/enzimología , Discapacidad Intelectual/genética , Trastornos del Neurodesarrollo/enzimología , Trastornos del Neurodesarrollo/genética , Convulsiones/enzimología , Convulsiones/genética , Animales , Trastorno del Espectro Autista/genética , Deleción Cromosómica , Cromosomas Humanos Par 15/enzimología , Cromosomas Humanos Par 15/genética , Espinas Dendríticas/metabolismo , Enzimas Desubicuitinizantes/genética , Endopeptidasas/metabolismo , Femenino , Eliminación de Gen , Estudios de Asociación Genética , Humanos , Masculino , Ratones , Fenotipo , Prosencéfalo/patología
3.
Neural Plast ; 2016: 7694385, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27847649

RESUMEN

Cortical inhibitory neurons play crucial roles in regulating excitatory synaptic networks and cognitive function and aberrant development of these cells have been linked to neurodevelopmental disorders. The secreted neurotrophic factor Neuregulin-1 (NRG1) and its receptor ErbB4 are established regulators of inhibitory neuron connectivity, but the developmental signalling mechanisms regulating this process remain poorly understood. Here, we provide evidence that NRG1-ErbB4 signalling functions through the multifunctional scaffold protein, Disrupted in Schizophrenia 1 (DISC1), to regulate the development of cortical inhibitory interneuron dendrite and synaptic growth. We found that NRG1 increases inhibitory neuron dendrite complexity and glutamatergic synapse formation onto inhibitory neurons and that this effect is blocked by expression of a dominant negative DISC1 mutant, or DISC1 knockdown. We also discovered that NRG1 treatment increases DISC1 expression and its localization to glutamatergic synapses being made onto cortical inhibitory neurons. Mechanistically, we determined that DISC1 binds ErbB4 within cortical inhibitory neurons. Collectively, these data suggest that a NRG1-ErbB4-DISC1 signalling pathway regulates the development of cortical inhibitory neuron dendrite and synaptic growth. Given that NRG1, ErbB4, and DISC1 are schizophrenia-linked genes, these findings shed light on how independent risk factors may signal in a common developmental pathway that contributes to neural connectivity defects and disease pathogenesis.


Asunto(s)
Corteza Cerebral/fisiología , Dendritas/fisiología , Proteínas del Tejido Nervioso/biosíntesis , Neurregulina-1/farmacología , Neuronas/fisiología , Sinapsis/fisiología , Animales , Células Cultivadas , Corteza Cerebral/citología , Corteza Cerebral/efectos de los fármacos , Dendritas/efectos de los fármacos , Células HEK293 , Humanos , Ratones , Inhibición Neural/efectos de los fármacos , Inhibición Neural/fisiología , Neurogénesis/efectos de los fármacos , Neurogénesis/fisiología , Neuronas/efectos de los fármacos , Sinapsis/efectos de los fármacos
4.
Cell Rep ; 41(8): 111678, 2022 11 22.
Artículo en Inglés | MEDLINE | ID: mdl-36417873

RESUMEN

There are hundreds of risk genes associated with autism spectrum disorder (ASD), but signaling networks at the protein level remain unexplored. We use neuron-specific proximity-labeling proteomics (BioID2) to identify protein-protein interaction (PPI) networks for 41 ASD risk genes. Neuron-specific PPI networks, including synaptic transmission proteins, are disrupted by de novo missense variants. The PPI network map reveals convergent pathways, including mitochondrial/metabolic processes, Wnt signaling, and MAPK signaling. CRISPR knockout displays an association between mitochondrial activity and ASD risk genes. The PPI network shows an enrichment of 112 additional ASD risk genes and differentially expressed genes from postmortem ASD patients. Clustering of risk genes based on PPI networks identifies gene groups corresponding to clinical behavior score severity. Our data report that cell type-specific PPI networks can identify individual and convergent ASD signaling networks, provide a method to assess patient variants, and highlight biological insight into disease mechanisms and sub-cohorts of ASD.


Asunto(s)
Trastorno del Espectro Autista , Trastorno Autístico , Humanos , Trastorno Autístico/genética , Trastorno del Espectro Autista/genética , Mapas de Interacción de Proteínas/genética , Neuronas , Proteínas , Vía de Señalización Wnt
5.
J Neurodev Disord ; 8: 45, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27980692

RESUMEN

BACKGROUND: Genetic factors play a major role in the risk for neurodevelopmental disorders such as autism spectrum disorders (ASDs) and intellectual disability (ID). The underlying genetic factors have become better understood in recent years due to advancements in next generation sequencing. These studies have uncovered a vast number of genes that are impacted by different types of mutations (e.g., de novo, missense, truncation, copy number variations). ABSTRACT: Given the large volume of genetic data, analyzing each gene on its own is not a feasible approach and will take years to complete, let alone attempt to use the information to develop novel therapeutics. To make sense of independent genomic data, one approach is to determine whether multiple risk genes function in common signaling pathways that identify signaling "hubs" where risk genes converge. This approach has led to multiple pathways being implicated, such as synaptic signaling, chromatin remodeling, alternative splicing, and protein translation, among many others. In this review, we analyze recent and historical evidence indicating that multiple risk genes, including genes denoted as high-confidence and likely causal, are part of the Wingless (Wnt signaling) pathway. In the brain, Wnt signaling is an evolutionarily conserved pathway that plays an instrumental role in developing neural circuits and adult brain function. CONCLUSIONS: We will also review evidence that pharmacological therapies and genetic mouse models further identify abnormal Wnt signaling, particularly at the synapse, as being disrupted in ASDs and contributing to disease pathology.

6.
Cell Rep ; 17(7): 1892-1904, 2016 11 08.
Artículo en Inglés | MEDLINE | ID: mdl-27829159

RESUMEN

The development of neural connectivity is essential for brain function, and disruption of this process is associated with autism spectrum disorders (ASDs). DIX domain containing 1 (DIXDC1) has previously been implicated in neurodevelopmental disorders, but its role in postnatal brain function remains unknown. Using a knockout mouse model, we determined that DIXDC1 is a regulator of excitatory neuron dendrite development and synapse function in the cortex. We discovered that MARK1, previously linked to ASDs, phosphorylates DIXDC1 to regulate dendrite and spine development through modulation of the cytoskeletal network in an isoform-specific manner. Finally, rare missense variants in DIXDC1 were identified in ASD patient cohorts via genetic sequencing. Interestingly, the variants inhibit DIXDC1 isoform 1 phosphorylation, causing impairment to dendrite and spine growth. These data reveal that DIXDC1 is a regulator of cortical dendrite and synaptic development and provide mechanistic insight into morphological defects associated with neurodevelopmental disorders.


Asunto(s)
Dendritas/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Mutación/genética , Animales , Trastorno Autístico/metabolismo , Trastorno Autístico/patología , Encéfalo/metabolismo , Espinas Dendríticas/metabolismo , Péptidos y Proteínas de Señalización Intracelular/deficiencia , Ratones Endogámicos C57BL , Ratones Noqueados , Microtúbulos/metabolismo , Mutación Missense/genética , Fosforilación , Isoformas de Proteínas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Sinapsis/metabolismo
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA