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1.
Nature ; 611(7936): 532-539, 2022 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-36323788

RESUMEN

Neuropsychiatric disorders classically lack defining brain pathologies, but recent work has demonstrated dysregulation at the molecular level, characterized by transcriptomic and epigenetic alterations1-3. In autism spectrum disorder (ASD), this molecular pathology involves the upregulation of microglial, astrocyte and neural-immune genes, the downregulation of synaptic genes, and attenuation of gene-expression gradients in cortex1,2,4-6. However, whether these changes are limited to cortical association regions or are more widespread remains unknown. To address this issue, we performed RNA-sequencing analysis of 725 brain samples spanning 11 cortical areas from 112 post-mortem samples from individuals with ASD and neurotypical controls. We find widespread transcriptomic changes across the cortex in ASD, exhibiting an anterior-to-posterior gradient, with the greatest differences in primary visual cortex, coincident with an attenuation of the typical transcriptomic differences between cortical regions. Single-nucleus RNA-sequencing and methylation profiling demonstrate that this robust molecular signature reflects changes in cell-type-specific gene expression, particularly affecting excitatory neurons and glia. Both rare and common ASD-associated genetic variation converge within a downregulated co-expression module involving synaptic signalling, and common variation alone is enriched within a module of upregulated protein chaperone genes. These results highlight widespread molecular changes across the cerebral cortex in ASD, extending beyond association cortex to broadly involve primary sensory regions.


Asunto(s)
Trastorno del Espectro Autista , Corteza Cerebral , Variación Genética , Transcriptoma , Humanos , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/metabolismo , Trastorno del Espectro Autista/patología , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Neuronas/metabolismo , ARN/análisis , ARN/genética , Transcriptoma/genética , Autopsia , Análisis de Secuencia de ARN , Corteza Visual Primaria/metabolismo , Neuroglía/metabolismo
2.
J Neurosci ; 42(8): 1587-1603, 2022 02 23.
Artículo en Inglés | MEDLINE | ID: mdl-34987109

RESUMEN

Astrocytes are critical for the development and function of synapses. There are notable species differences between human astrocytes and commonly used animal models. Yet, it is unclear whether astrocytic genes involved in synaptic function are stable or exhibit dynamic changes associated with disease states and age in humans, which is a barrier in understanding human astrocyte biology and its potential involvement in neurologic diseases. To better understand the properties of human astrocytes, we acutely purified astrocytes from the cerebral cortices of over 40 humans across various ages, sexes, and disease states. We performed RNA sequencing to generate transcriptomic profiles of these astrocytes and identified genes associated with these biological variables. We found that human astrocytes in tumor-surrounding regions downregulate genes involved in synaptic function and sensing of signals in the microenvironment, suggesting involvement of peritumor astrocytes in tumor-associated neural circuit dysfunction. In aging, we also found downregulation of synaptic regulators and upregulation of markers of cytokine signaling, while in maturation we identified changes in ionic transport with implications for calcium signaling. In addition, we identified subtle sexual dimorphism in human cortical astrocytes, which has implications for observed sex differences across many neurologic disorders. Overall, genes involved in synaptic function exhibit dynamic changes in the peritumor microenvironment and aging. These data provide powerful new insights into human astrocyte biology in several biologically relevant states that will aid in generating novel testable hypotheses about homeostatic and reactive astrocytes in humans.SIGNIFICANCE STATEMENT Astrocytes are an abundant class of cells playing integral roles at synapses. Astrocyte dysfunction is implicated in a variety of human neurologic diseases. Yet our knowledge of astrocytes is largely based on mouse studies. Direct knowledge of human astrocyte biology remains limited. Here, we present transcriptomic profiles of human cortical astrocytes, and we identified molecular differences associated with age, sex, and disease state. We found that peritumor and aging astrocytes downregulate genes involved in astrocyte-synapse interactions. These data provide necessary insight into human astrocyte biology that will improve our understanding of human disease.


Asunto(s)
Astrocitos , Transcriptoma , Envejecimiento/patología , Animales , Astrocitos/fisiología , Femenino , Humanos , Masculino , Ratones , Sinapsis/fisiología , Microambiente Tumoral
3.
Nat Commun ; 13(1): 3328, 2022 06 09.
Artículo en Inglés | MEDLINE | ID: mdl-35680911

RESUMEN

Gene expression covaries with brain activity as measured by resting state functional magnetic resonance imaging (MRI). However, it is unclear how genomic differences driven by disease state can affect this relationship. Here, we integrate from the ABIDE I and II imaging cohorts with datasets of gene expression in brains of neurotypical individuals and individuals with autism spectrum disorder (ASD) with regionally matched brain activity measurements from fMRI datasets. We identify genes linked with brain activity whose association is disrupted in ASD. We identified a subset of genes that showed a differential developmental trajectory in individuals with ASD compared with controls. These genes are enriched in voltage-gated ion channels and inhibitory neurons, pointing to excitation-inhibition imbalance in ASD. We further assessed differences at the regional level showing that the primary visual cortex is the most affected region in ASD. Our results link disrupted brain expression patterns of individuals with ASD to brain activity and show developmental, cell type, and regional enrichment of activity linked genes.


Asunto(s)
Trastorno del Espectro Autista , Trastorno del Espectro Autista/diagnóstico por imagen , Trastorno del Espectro Autista/genética , Encéfalo/diagnóstico por imagen , Mapeo Encefálico/métodos , Expresión Génica , Humanos , Imagen por Resonancia Magnética/métodos , Vías Nerviosas
4.
Stem Cell Reports ; 17(10): 2220-2238, 2022 10 11.
Artículo en Inglés | MEDLINE | ID: mdl-36179695

RESUMEN

Telencephalic organoids generated from human pluripotent stem cells (hPSCs) are a promising system for studying the distinct features of the developing human brain and the underlying causes of many neurological disorders. While organoid technology is steadily advancing, many challenges remain, including potential batch-to-batch and cell-line-to-cell-line variability, and structural inconsistency. Here, we demonstrate that a major contributor to cortical organoid quality is the way hPSCs are maintained prior to differentiation. Optimal results were achieved using particular fibroblast-feeder-supported hPSCs rather than feeder-independent cells, differences that were reflected in their transcriptomic states at the outset. Feeder-supported hPSCs displayed activation of diverse transforming growth factor ß (TGFß) superfamily signaling pathways and increased expression of genes connected to naive pluripotency. We further identified combinations of TGFß-related growth factors that are necessary and together sufficient to impart broad telencephalic organoid competency to feeder-free hPSCs and enhance the formation of well-structured brain tissues suitable for disease modeling.


Asunto(s)
Organoides , Células Madre Pluripotentes , Diferenciación Celular/fisiología , Humanos , Organoides/metabolismo , Células Madre Pluripotentes/metabolismo , Telencéfalo/metabolismo , Factor de Crecimiento Transformador beta/metabolismo
5.
Biol Psychiatry ; 89(1): 54-64, 2021 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-32792264

RESUMEN

Over the past decade, large-scale genetic studies have successfully identified hundreds of genetic variants robustly associated with risk for psychiatric disorders. However, mechanistic insight and clinical translation continue to lag the pace of risk variant identification, hindered by the sheer number of targets and their predominant noncoding localization, as well as pervasive pleiotropy and incomplete penetrance. Successful next steps require identification of "causal" genetic variants and their proximal biological consequences; placing variants within biologically defined functional contexts, reflecting specific molecular pathways, cell types, circuits, and developmental windows; and characterizing the downstream, convergent neurobiological impact of polygenicity within an individual. Here, we discuss opportunities and challenges of high-throughput transcriptomic profiling in the human brain, and how transcriptomic approaches can help pinpoint mechanisms underlying genetic risk for psychiatric disorders at a scale necessary to tackle daunting levels of polygenicity. These include transcriptome-wide association studies for risk gene prioritization through integration of genome-wide association studies with expression quantitative trait loci. We outline transcriptomic results that inform our understanding of the brain-level molecular pathology of psychiatric disorders, including autism spectrum disorder, bipolar disorder, major depressive disorder, and schizophrenia. Finally, we discuss systems-level approaches for integration of distinct genetic, genomic, and phenotypic levels, including combining spatially resolved gene expression and human neuroimaging maps. Results highlight the importance of understanding gene expression (dys)regulation across human brain development as a major contributor to psychiatric disease pathogenesis, from common variants acting as expression quantitative trait loci to rare variants enriched for gene expression regulatory pathways.


Asunto(s)
Trastorno del Espectro Autista , Trastorno Depresivo Mayor , Trastorno Depresivo Mayor/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Herencia Multifactorial , Transcriptoma
6.
Nat Neurosci ; 24(6): 799-809, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33958802

RESUMEN

The most significant common variant association for schizophrenia (SCZ) reflects increased expression of the complement component 4A (C4A). Yet, it remains unclear how C4A interacts with other SCZ risk genes or whether the complement system more broadly is implicated in SCZ pathogenesis. Here, we integrate several existing, large-scale genetic and transcriptomic datasets to interrogate the functional role of the complement system and C4A in the human brain. Unexpectedly, we find no significant genetic enrichment among known complement system genes for SCZ. Conversely, brain co-expression network analyses using C4A as a seed gene reveal that genes downregulated when C4A expression increases exhibit strong and specific genetic enrichment for SCZ risk. This convergent genomic signal reflects synaptic processes, is sexually dimorphic and most prominent in frontal cortical brain regions, and is accentuated by smoking. Overall, these results indicate that synaptic pathways-rather than the complement system-are the driving force conferring SCZ risk.


Asunto(s)
Encéfalo/patología , Redes Reguladoras de Genes/genética , Predisposición Genética a la Enfermedad/genética , Esquizofrenia/genética , Esquizofrenia/patología , Sinapsis/patología , Bases de Datos Genéticas , Femenino , Expresión Génica , Estudio de Asociación del Genoma Completo/métodos , Humanos , Masculino , Estudios Retrospectivos , Transducción de Señal/genética
7.
JCI Insight ; 4(17)2019 09 05.
Artículo en Inglés | MEDLINE | ID: mdl-31484827

RESUMEN

Deficiency of arginase is associated with hyperargininemia, and prominent features include spastic diplegia/tetraplegia, clonus, and hyperreflexia; loss of ambulation, intellectual disability and progressive neurological decline are other signs. To gain greater insight into the unique neuromotor features, we performed gene expression profiling of the motor cortex of a murine model of the disorder. Coexpression network analysis suggested an abnormality with myelination, which was supported by limited existing human data. Utilizing electron microscopy, marked dysmyelination was detected in 2-week-old homozygous Arg1-KO mice. The corticospinal tract was found to be adversely affected, supporting dysmyelination as the cause of the unique neuromotor features and implicating oligodendrocyte impairment in a deficiency of hepatic Arg1. Following neonatal hepatic gene therapy to express Arg1, the subcortical white matter, pyramidal tract, and corticospinal tract all showed a remarkable recovery in terms of myelinated axon density and ultrastructural integrity with active wrapping of axons by nearby oligodendrocyte processes. These findings support the following conclusions: arginase deficiency is a leukodystrophy affecting the brain and spinal cord while sparing the peripheral nervous system, and neonatal AAV hepatic gene therapy can rescue the defects associated with myelinated axons, strongly implicating the functional recovery of oligodendrocytes after restoration of hepatic arginase activity.


Asunto(s)
Arginasa/genética , Predisposición Genética a la Enfermedad/genética , Hiperargininemia/genética , Hiperargininemia/metabolismo , Hígado/enzimología , Hígado/metabolismo , Animales , Arginasa/metabolismo , Axones/metabolismo , Axones/patología , Sistema Nervioso Central/diagnóstico por imagen , Sistema Nervioso Central/patología , Modelos Animales de Enfermedad , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Terapia Genética , Homocigoto , Hiperargininemia/patología , Masculino , Ratones , Ratones Noqueados , Oligodendroglía/metabolismo , Transcriptoma
8.
Focus (Am Psychiatr Publ) ; 17(1): 66-72, 2019 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-32015716

RESUMEN

(Gandal et al., "Shared molecular neuropathology across major psychiatric disorders parallels polygenic overlap" Science 09 Feb 2018:Vol. 359, Issue 6376, pp. 693-697 (DOI: 10.1126/science.aad6469). Reprinted with permission from AAAS).

9.
Science ; 359(6376): 693-697, 2018 02 09.
Artículo en Inglés | MEDLINE | ID: mdl-29439242

RESUMEN

The predisposition to neuropsychiatric disease involves a complex, polygenic, and pleiotropic genetic architecture. However, little is known about how genetic variants impart brain dysfunction or pathology. We used transcriptomic profiling as a quantitative readout of molecular brain-based phenotypes across five major psychiatric disorders-autism, schizophrenia, bipolar disorder, depression, and alcoholism-compared with matched controls. We identified patterns of shared and distinct gene-expression perturbations across these conditions. The degree of sharing of transcriptional dysregulation is related to polygenic (single-nucleotide polymorphism-based) overlap across disorders, suggesting a substantial causal genetic component. This comprehensive systems-level view of the neurobiological architecture of major neuropsychiatric illness demonstrates pathways of molecular convergence and specificity.


Asunto(s)
Predisposición Genética a la Enfermedad , Trastornos Mentales/genética , Herencia Multifactorial , Enfermedades del Sistema Nervioso/genética , Corteza Cerebral/metabolismo , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Humanos , Polimorfismo de Nucleótido Simple , Transcripción Genética
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