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1.
Genome Med ; 12(1): 34, 2020 04 19.
Artículo en Inglés | MEDLINE | ID: mdl-32306996

RESUMEN

BACKGROUND: Reprogramming human induced pluripotent stem cells (iPSCs) from somatic cells and generating three-dimensional brain organoids from these iPSCs provide access to live human neuronal tissue with disease-specific genetic backgrounds. METHODS: Cerebral organoids were generated from iPSCs of eight bipolar disorder (BPI) patients and eight healthy control individuals. RNA-seq experiments were undertaken using RNA isolated from the cerebral organoids. Functional activity in the cerebral organoids was studied using microelectrode arrays. RESULTS: RNA-seq data comparing gene expression profiles in the cerebral organoids showed downregulation of pathways involved in cell adhesion, neurodevelopment, and synaptic biology in bipolar disorder along with upregulation of genes involved in immune signaling. The central hub in the network analysis was neurocan (NCAN), which is located in a locus with evidence for genome-wide significant association in BPI. Gene ontology analyses suggested deficits related to endoplasmic reticulum biology in BPI, which was supported by cellular characterization of ER-mitochondria interactions. Functional studies with microelectrode arrays revealed specific deficits in response to stimulation and depolarization in BPI cerebral organoids. CONCLUSIONS: Our studies in cerebral organoids from bipolar disorder showed dysregulation in genes involved in cell adhesion, immune signaling, and endoplasmic reticulum biology; implicated a central role for the GWAS hit NCAN in the biology of BPI; and showed evidence of deficits in neurotransmission.


Asunto(s)
Trastorno Bipolar/genética , Células-Madre Neurales/metabolismo , Organoides/metabolismo , Transcriptoma , Adulto , Trastorno Bipolar/metabolismo , Adhesión Celular , Células Cultivadas , Proteoglicanos Tipo Condroitín Sulfato/genética , Proteoglicanos Tipo Condroitín Sulfato/metabolismo , Femenino , Humanos , Células Madre Pluripotentes Inducidas/citología , Células Madre Pluripotentes Inducidas/metabolismo , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Masculino , Potenciales de la Membrana , Persona de Mediana Edad , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Células-Madre Neurales/citología , Células-Madre Neurales/fisiología , Neurocano , Organoides/citología , Organoides/fisiología
3.
Sci Rep ; 7: 44277, 2017 03 10.
Artículo en Inglés | MEDLINE | ID: mdl-28281674

RESUMEN

Cationic amphiphilic drugs (CADs) comprise a wide variety of different substance classes such as antidepressants, antipsychotics, and antiarrhythmics. It is well recognized that CADs accumulate in certain intracellular compartments leading to specific morphological changes of cells. So far, no adequate technique exists allowing for ultrastructural analysis of CAD in intact cells. Azidobupramine, a recently described multifunctional antidepressant analogue, allows for the first time to perform high-resolution studies of CADs on distribution pattern and morphological changes in intact cells. We showed here that the intracellular distribution pattern of azidobupramine strongly depends on drug concentration and exposure time. The mitochondrial compartment (mDsRed) and the late endo-lysosomal compartment (CD63-GFP) were the preferred localization sites at low to intermediate concentrations (i.e. 1 µM, 5 µM). In contrast, the autophagosomal compartment (LC3-GFP) can only be reached at high concentrations (10 µM) and long exposure times (72 hrs). At the morphological level, LC3-clustering became only prominent at high concentrations (10 µM), while changes in CD63 pattern already occurred at intermediate concentrations (5 µM). To our knowledge, this is the first study that establishes a link between intracellular CAD distribution pattern and morphological changes. Therewith, our results allow for gaining deeper understanding of intracellular effects of CADs.


Asunto(s)
Antidepresivos Tricíclicos/metabolismo , Cationes/metabolismo , Espacio Intracelular/metabolismo , Preparaciones Farmacéuticas/metabolismo , Antidepresivos Tricíclicos/química , Antidepresivos Tricíclicos/farmacocinética , Autofagosomas/metabolismo , Cationes/química , Cationes/farmacocinética , Células HeLa , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Lisosomas/metabolismo , Mitocondrias/metabolismo , Preparaciones Farmacéuticas/química
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