Integrative analysis identifies key molecular signatures underlying neurodevelopmental deficits in fragile X syndrome

Utami, Kagistia Hana; Skotte, Niels H.; Colaço, Ana R.; Yusof, Nur Amirah Binte Mohammad; Sim, Bernice; Yeo, Xin Yi; Bae, Han‐Gyu; Garcia-Miralles, Marta; Radulescu, Carola I.; Chen, Qiyu; Chaldaiopoulou, Georgia; Liany, Herty; Nama, Srikanth; Sampath, Prabha; Jung, Sangyong; Mann, Matthias; Pouladi, Mahmoud A.

doi:10.1101/606038

Cited by 2 publications

(2 citation statements)

References 71 publications

(22 reference statements)

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“…Finally, many of the neuronal downregulated pathways including neuron projection terms and vesicle transport were identified as downregulated both in RNA and protein levels by recent studies in human in-vitro neurons derived from embryonic or pluripotent stem cells [99][100][101] . This suggests that the downstream molecular consequences of the absence of FMRP in neurons are well conserved and that the wealth of altered pathways we observed in the Fmr1 -KO mouse model can provide a valuable resource for future studies in FXS patients and the design of therapeutic approaches.…”

Section: Discussionmentioning

confidence: 99%

Single Cell Transcriptomics Reveals Dysregulated Cellular and Molecular Networks in a Fragile X Syndrome model

Donnard

Shu

Garber

2020

Preprint

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Despite advances in understanding the pathophysiology of Fragile X syndrome (FXS), its molecular bases are still poorly understood. Whole brain tissue expression profiles have proved surprisingly uninformative. We applied single cell RNA sequencing to profile a FXS mouse model. We found that FXS results in a highly cell type specific effect and it is strongest among different neuronal types. We detected a downregulation of mRNAs bound by FMRP and this effect is prominent in neurons. Metabolic pathways including translation are significantly upregulated across all cell types with the notable exception of excitatory neurons. These effects point to a potential difference in the activity of mTOR pathways, and together with other dysregulated pathways suggest an excitatory-inhibitory imbalance in the FXS cortex which is exacerbated by astrocytes. Our data demonstrate the cell-type specific complexity of FXS and provide a resource for interrogating the biological basis of this disorder.

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Section: Discussionmentioning

confidence: 99%

Single Cell Transcriptomics Reveals Dysregulated Cellular and Molecular Networks in a Fragile X Syndrome model

Donnard

Shu

Garber

2020

Preprint

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“…Disrupted glutamatergic signaling plays a critical role in the pathogenesis of SCZ 41 . Consistently, on several levels, our data provide evidence supporting the idea that glutamatergic neurons are the main contributors for the network phenotype caused by SETD1A haploinsufficiency.…”

Section: Discussionmentioning

confidence: 99%

Loss-of-function variants in the schizophrenia risk gene SETD1A alter neuronal network activity in human neurons through cAMP/PKA pathway

Wang

Rhijn

Akkouh

et al. 2021

Preprint

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Heterozygous loss-of-function (LoF) mutations in SETD1A, which encodes a subunit of histone H3 lysine 4 methyltransferase, have been shown to cause a novel neurodevelopmental syndrome and increase the risk for schizophrenia. To study the effect of decreased SETD1A function in human cells, we generated excitatory/inhibitory neuronal networks from human induced pluripotent stem cells with a SETD1A heterozygous LoF mutation (SETD1A+/-). Our data show that SETD1A haploinsufficiency resulted in altered neuronal network activity, which was mainly characterized by an overly synchronized network. In individual neurons, this network phenotype was reflected by increased somatodendritic complexity and elevated synaptic connectivity. We found that this network phenotype was driven by SETD1A haploinsufficiency in glutamatergic neurons. In accordance with the functional changes, transcriptomic profiling revealed perturbations in gene sets associated with schizophrenia, synaptic transmission and glutamatergic synaptic function. At the molecular level, we identified specific changes in the cAMP/PKA pathway pointing toward a hyperactive cAMP pathway in SETD1A+/- neurons. Finally, using pharmacological experiments targeting the cAMP pathway we were able to rescue the network deficits in SETD1A+/- cultures. In conclusion, our results illuminate key molecular, cellular and network abnormalities caused by SETD1A haploinsufficiency and demonstrate a direct link between SETD1A and the cAMP-dependent pathway in human neurons.

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Integrative analysis identifies key molecular signatures underlying neurodevelopmental deficits in fragile X syndrome

Cited by 2 publications

References 71 publications

Single Cell Transcriptomics Reveals Dysregulated Cellular and Molecular Networks in a Fragile X Syndrome model

Single Cell Transcriptomics Reveals Dysregulated Cellular and Molecular Networks in a Fragile X Syndrome model

Loss-of-function variants in the schizophrenia risk gene SETD1A alter neuronal network activity in human neurons through cAMP/PKA pathway

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