Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1308459 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Eukaryotic cells maintain proteostasis through mechanisms that require cytoplasmic and mitochondrial translation. Genetic defects affecting cytoplasmic translation perturb synapse development, neurotransmission, and are causative of neurodevelopmental disorders such as Fragile X syndrome. In contrast, there is little indication that mitochondrial proteostasis, either in the form of mitochondrial protein translation and/or degradation, is required for synapse development and function. Here we focus on two genes deleted in a recurrent copy number variation causing neurodevelopmental disorders, the 22q11.2 microdeletion syndrome. We demonstrate that SLC25A1 and MRPL40, two genes present in the microdeleted segment and whose products localize to mitochondria, interact and are necessary for mitochondrial ribosomal integrity and proteostasis. Our Drosophila studies show that mitochondrial ribosome function is necessary for synapse neurodevelopment, function, and behavior. We propose that mitochondrial proteostasis perturbations, either by genetic or environmental factors, are a pathogenic mechanism for neurodevelopmental disorders.
2022-02-17 | PXD025289 | Pride
Project description:Alterations in cortical neurogenesis are implicated in neurodevelopmental disorders including autism spectrum disorders (ASDs). Many ASD risk genes have been identified as critical for brain development, but the contribution of genetic backgrounds, although inferred in complex genetic disorders such as ASD, remains unclear. Here, using isogenic induced pluripotent stem cell (iPSC)-derived neural progenitor cells (NPCs) and cortical organoid models, we report that a heterozygous PTEN p.I135L mutation found in an ASD patient with macrocephaly dysregulates cortical neurogenesis in an ASD genetic background-dependent fashion. We found that this PTEN p.I135L mutation led to overproduction of NPC subtypes as well as neuronal subtypes including both deep and upper layer neurons in its ASD background, but not when introduced into a control genetic background. ASD and control background differences in neurogenesis, neural development and synapse signaling were also observed. These findings provide experimental evidence that both a PTEN p.I135L mutation and ASD genetic background contribute to cellular features consistent with ASD associated with macrocephaly.
2023-03-20 | GSE221882 | GEO
Project description:Alterations in cortical neurogenesis are implicated in neurodevelopmental disorders including autism spectrum disorders (ASDs). Many ASD risk genes have been identified as critical for brain development, but the contribution of genetic backgrounds, although inferred in complex genetic disorders such as ASD, remains unclear. Here, using isogenic induced pluripotent stem cell (iPSC)-derived neural progenitor cells (NPCs) and cortical organoid models, we report that a heterozygous PTEN p.I135L mutation found in an ASD patient with macrocephaly dysregulates cortical neurogenesis in an ASD genetic background-dependent fashion. We found that this PTEN p.I135L mutation led to overproduction of NPC subtypes as well as neuronal subtypes including both deep and upper layer neurons in its ASD background, but not when introduced into a control genetic background. ASD and control background differences in neurogenesis, neural development and synapse signaling were also observed. These findings provide experimental evidence that both a PTEN p.I135L mutation and ASD genetic background contribute to cellular features consistent with ASD associated with macrocephaly.
2023-03-20 | GSE214422 | GEO
Project description:Alterations in cortical neurogenesis are implicated in neurodevelopmental disorders including autism spectrum disorders (ASDs). Many ASD risk genes have been identified as critical for brain development, but the contribution of genetic backgrounds, although inferred in complex genetic disorders such as ASD, remains unclear. Here, using isogenic induced pluripotent stem cell (iPSC)-derived neural progenitor cells (NPCs) and cortical organoid models, we report that a heterozygous PTEN p.I135L mutation found in an ASD patient with macrocephaly dysregulates cortical neurogenesis in an ASD genetic background-dependent fashion. We found that this PTEN p.I135L mutation led to overproduction of NPC subtypes as well as neuronal subtypes including both deep and upper layer neurons in its ASD background, but not when introduced into a control genetic background. ASD and control background differences in neurogenesis, neural development and synapse signaling were also observed. These findings provide experimental evidence that both a PTEN p.I135L mutation and ASD genetic background contribute to cellular features consistent with ASD associated with macrocephaly.
2023-03-20 | GSE214323 | GEO
Project description:Alterations in cortical neurogenesis are implicated in neurodevelopmental disorders including autism spectrum disorders (ASDs). Many ASD risk genes have been identified as critical for brain development, but the contribution of genetic backgrounds, although inferred in complex genetic disorders such as ASD, remains unclear. Here, using isogenic induced pluripotent stem cell (iPSC)-derived neural progenitor cells (NPCs) and cortical organoid models, we report that a heterozygous PTEN p.I135L mutation found in an ASD patient with macrocephaly dysregulates cortical neurogenesis in an ASD genetic background-dependent fashion. We found that this PTEN p.I135L mutation led to overproduction of NPC subtypes as well as neuronal subtypes including both deep and upper layer neurons in its ASD background, but not when introduced into a control genetic background. ASD and control background differences in neurogenesis, neural development and synapse signaling were also observed. These findings provide experimental evidence that both a PTEN p.I135L mutation and ASD genetic background contribute to cellular features consistent with ASD associated with macrocephaly.
2023-03-20 | GSE221923 | GEO
Project description:<p>Omega-3 fatty acids (n-3 polyunsaturated fatty acids; n-3 PUFAs) are essential for the functional maturation of the brain. Westernization of dietary habits in both developed and developing countries is accompanied by a progressive reduction in dietary intake of n-3 PUFAs. Low maternal intake of n-3 PUFAs has been linked to neurodevelopmental diseases in epidemiological studies, but the mechanisms by which a n-3 PUFA dietary imbalance affects CNS development are poorly understood. Active microglial engulfment of synaptic elements is an important process for normal brain development and altered synapse refinement is a hallmark of several neurodevelopmental disorders. Here, we identify a molecular mechanism for detrimental effects of low maternal n-3 PUFA intake on hippocampal development. Our results show that maternal dietary n-3 PUFA deficiency increases microglial phagocytosis of synaptic elements in the developing hippocampus, partly through the activation of 12/15- lipoxygenase (LOX)/12-HETE signaling, which alters neuronal morphology and affects cognition in the postnatal offspring. While women of child bearing age are at higher risk of dietary n-3 PUFA deficiency, these findings provide new insights into the mechanisms linking maternal nutrition to neurodevelopmental disorders.</p>
2020-11-03 | MTBLS1952 | MetaboLights
Project description:Dix domain containing 1 (Dixdc1) is an important regulator of neuronal development including cortical neurogenesis, neuronal migration and synaptic connectivity, and sequence variants in the gene have been linked to autism spectrum disorders (ASD). Previous studies indicate that Dixdc1 controls neurogenesis through Wnt signaling, while its regulation of dendrite and synapse development requires Wnt and cytoskeletal signaling. However, the prediction of these signaling pathways is primarily based on the structure of Dixdc1. Given the role of Dixdc1 in neural development and brain disorders, we hypothesized that Dixdc1 may regulate additional signaling pathways in the brain. We performed proteomic analyses of Dixdc1 KO mouse cortices to reveal such alterations.
2020-12-21 | PXD016995 | Pride
Project description:Biallelic genetic variants in N-acetylneuraminic acid synthase (NANS), a critical enzyme in endogenous sialic acid biosynthesis, are clinically associated with neurodevelopmental disorders. However, the mechanism underlying the neuropathological consequences has remained elusive. Here, we discovered that NANS mutation resulted in absence of both sialic acid and protein polysialylation in the cortical organoids and significantly reduced the proliferation and expansion of neural progenitors. NANS mutation dysregulated neural migration and differentiation, disturbed synapse formation, and weakened neuronal activity. Single-cell RNA sequencing revealed that NANS loss-of-function markedly altered transcriptional programs involved in neuronal differentiation and ribosomal biogenesis in various neuronal cell types. Similarly, Nans heterozygous mice exhibited impaired cortical neurogenesis and neurobehavioral deficits. Collectively, our findings reveal a crucial role of NANS-mediated endogenous sialic acid biosynthesis in regulating multiple features of human cortical development, thus linking NANS mutation with its clinically relevant neurodevelopmental disorders.
2023-06-26 | GSE233460 | GEO
Project description:The pathophysiology of neurodevelopmental disorders involves vulnerable neural populations, including striatal circuitry, and convergent molecular nodes, including chromatin regulation and synapse function. Despite this, how epigenetic regulation regulates striatal development is understudied. Recurrent de novo mutations in Zswim6 are associated with intellectual disability and autism. We demonstrate that ZSWIM6 localizes to the nucleus where it associates with repressive chromatin regulators. Disruption of Zswim6 in ventral telencephalic progenitors leads to increased chromatin accessibility and transcriptional dysregulation. Ablating Zswim6 in either striatal direct or indirect pathway spiny projection neurons resulted in similar cell-autonomous changes in excitatory but not inhibitory synaptic transmission. Specifically, Zswim6 disruption altered the desensitization properties of AMPA receptors, leading to enhanced synaptic recruitment of SPNs, explaining SPN-subtype specific effects on activity and behavioral sub-structure. Finally, adult deletion of Zswim6 identified a continuing role in the maintenance of mature striatal synapses. Together, we describe a mechanistic role for Zswim6 in the epigenetic control of striatal synaptic development.
2024-11-25 | GSE282824 | GEO