Modeling common and rare genetic risk factors of neuropsychiatric disorders in human induced pluripotent stem cells

Muhtaseb, Abdurrahman W; Duan, Jubao

doi:10.1016/j.schres.2022.04.003

Cited by 8 publications

(13 citation statements)

References 285 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although CRISPR editing of individual NPD risk genes/variants in hiPSC has been widely used in the past decade (De Los Angeles et al ., 2021; Duan, 2023; Michael Deans and Brennand, 2021; Muhtaseb and Duan, 2022; Wang et al ., 2020; Wen et al ., 2016; Zhang et al ., 2023; Zhang et al, 2020), a scaled and efficient pipeline for clonal LoF mutagenesis in hiPSC has not been established. Our reported CBE iSTOP editing workflow benefited from the improved gene editing efficiency of the CBEmax_enrich system, the precision of iSTOP mutagenesis, the streamlined RNA-seq-based assays for pluripotency, eSNP-Karyotyping, and iSTOP-mediated NMD and/or LoF.…”

Section: Discussionmentioning

confidence: 99%

“…Human induced pluripotent stem cells (hiPSC) and their derived neural cells empowered by CRISPR-mediated gene editing provide promising cellular models for studying NPD genes (De Los Angeles et al, 2021; Duan, 2023; Michael Deans and Brennand, 2021; Muhtaseb and Duan, 2022; Wang et al, 2020; Wen et al, 2016) and for scaling up the assay. A “cell village” approach (Wells et al, 2023) enables the co-culture of tens to hundreds of hiPSC lines in a dish and to differentiate them into neurons together, followed by assaying a specific cellular phenotype and genetically inferring individual cell identity.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Scaled and Efficient Derivation of Loss of Function Alleles in Risk Genes for Neurodevelopmental and Psychiatric Disorders in Human iPSC

Zhang,

Peyton,

McCarroll

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

Translating genetic findings for neurodevelopmental and psychiatric disorders (NPD) into actionable disease biology would benefit from large-scale and unbiased functional studies of NPD genes. Leveraging the cytosine base editing (CBE) system, here we developed a pipeline for clonal loss-of-function (LoF) allele mutagenesis in human induced pluripotent stem cells (hiPSCs) by introducing premature stop-codons (iSTOP) that lead to mRNA nonsense-mediated-decay (NMD) or protein truncation. We tested the pipeline for 23 NPD genes on 3 hiPSC lines and achieved highly reproducible, efficient iSTOP editing in 22 NPD genes. Using RNAseq, we confirmed their pluripotency, absence of chromosomal abnormalities, and NMD. Interestingly, for three schizophrenia risk genes (SETD1A, TRIO, CUL1), despite the high efficiency of base editing, we only obtained heterozygous LoF alleles, suggesting their essential roles for cell growth. We replicated the reported neural phenotypes of SHANK3-haploinsufficiency and found CUL1-LoF reduced neurite branches and synaptic puncta density. This iSTOP pipeline enables a scaled and efficient LoF mutagenesis of NPD genes, yielding an invaluable shareable resource.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Scaled and Efficient Derivation of Loss of Function Alleles in Risk Genes for Neurodevelopmental and Psychiatric Disorders in Human iPSC

Zhang,

Peyton,

McCarroll

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Recent studies for highly penetrant risk genes have led to intriguing new insights into cellular processes that may underlie the disease biology of schizophrenia [36,55,56]. The presence of common variants with small effect sizes makes it difficult to parse the roles of individual genes when the disease arises due to the combined effects of many different variants [57]. The ability to generate iPSCs from well-characterized schizophrenia patients and healthy subjects enables us to generate neuronal cells that have the same genetic background as the subjects and interrogate biological differences that result from the collective effect of the complex genetic backgrounds [58][59][60][61][62].…”

Section: Discussionmentioning

confidence: 99%

Morphological and transcriptomic analyses of stem cell-derived cortical neurons reveal mechanisms underlying synaptic dysfunction in schizophrenia

et al. 2023

View full text Add to dashboard Cite

Background Postmortem studies in schizophrenia consistently show reduced dendritic spines in the cerebral cortex but the mechanistic underpinnings of these deficits remain unknown. Recent genome-wide association studies and exome sequencing investigations implicate synaptic genes and processes in the disease biology of schizophrenia. Methods We generated human cortical pyramidal neurons by differentiating iPSCs of seven schizophrenia patients and seven healthy subjects, quantified dendritic spines and synapses in different cortical neuron subtypes, and carried out transcriptomic studies to identify differentially regulated genes and aberrant cellular processes in schizophrenia. Results Cortical neurons expressing layer III marker CUX1, but not those expressing layer V marker CTIP2, showed significant reduction in dendritic spine density in schizophrenia, mirroring findings in postmortem studies. Transcriptomic experiments in iPSC-derived cortical neurons showed that differentially expressed genes in schizophrenia were enriched for genes implicated in schizophrenia in genome-wide association and exome sequencing studies. Moreover, most of the differentially expressed genes implicated in schizophrenia genetic studies had lower expression levels in schizophrenia cortical neurons. Network analysis of differentially expressed genes led to identification of NRXN3 as a hub gene, and follow-up experiments showed specific reduction of the NRXN3 204 isoform in schizophrenia neurons. Furthermore, overexpression of the NRXN3 204 isoform in schizophrenia neurons rescued the spine and synapse deficits in the cortical neurons while knockdown of NRXN3 204 in healthy neurons phenocopied spine and synapse deficits seen in schizophrenia cortical neurons. The antipsychotic clozapine increased expression of the NRXN3 204 isoform in schizophrenia cortical neurons and rescued the spine and synapse density deficits. Conclusions Taken together, our findings in iPSC-derived cortical neurons recapitulate cell type-specific findings in postmortem studies in schizophrenia and have led to the identification of a specific isoform of NRXN3 that modulates synaptic deficits in schizophrenia neurons.

show abstract

“…Furthermore, despite the supportive genetic evidence for the involvement of lipidrelated genes in AD and NPDs, whether neural LDs, FFA, and cholesterol are correlated with peripheral plasma lipid levels and other clinical outcomes of AD and NPDs during disease progression is unknown. To address these challenging questions, besides the traditionally used postmortem brains and animal models, iPSC-derived neurons, astrocytes, and microglia may provide invaluable in vitro cellular models [184,187,[225][226][227][228][229][230][231] for studying cell type-specific lipids and LDs in the context of different disease states, which will significantly advance our understanding of how cell type-specific abnormal lipids contribute to the risk for AD and some NPDs. Some cellular lipid metrics may serve as biomarkers for early AD diagnosis and progression, and the downstream gene pathways of lipids and LDs may be promising targets for developing more tailored and effective treatments for AD.…”

Section: Conclusion and Perspectivementioning

confidence: 99%

Brain Lipids and Lipid Droplet Dysregulation in Alzheimer’s Disease and Neuropsychiatric Disorders

Zhao,

Zhang,

Sanders

et al. 2023

Complex Psychiatry

Self Cite

View full text Add to dashboard Cite

Background: Lipids are essential components of the structure and for the function of brain cells. The intricate balance of lipids, including phospholipids, glycolipids, cholesterol, cholesterol ester, and triglycerides, is crucial for maintaining normal brain function. The roles of lipids and lipid droplets and their relevance to neurodegenerative and neuropsychiatric disorders (NPDs) remain largely unknown. Summary: Here, we reviewed the basic role of lipid components as well as a specific lipid organelle, lipid droplets, in brain function, highlighting the potential impact of altered lipid metabolism in the pathogenesis of Alzheimer’s disease (AD) and NDPs. Key Messages: Brain lipid dysregulation plays a pivotal role in the pathogenesis and progression of neurodegenerative and NPDs including AD and schizophrenia. Understanding the cell type-specific mechanisms of lipid dysregulation in these diseases is crucial for identifying better diagnostic biomarkers and for developing therapeutic strategies aiming at restoring lipid homeostasis.

show abstract

Modeling common and rare genetic risk factors of neuropsychiatric disorders in human induced pluripotent stem cells

Cited by 8 publications

References 285 publications

Scaled and Efficient Derivation of Loss of Function Alleles in Risk Genes for Neurodevelopmental and Psychiatric Disorders in Human iPSC

Scaled and Efficient Derivation of Loss of Function Alleles in Risk Genes for Neurodevelopmental and Psychiatric Disorders in Human iPSC

Morphological and transcriptomic analyses of stem cell-derived cortical neurons reveal mechanisms underlying synaptic dysfunction in schizophrenia

Brain Lipids and Lipid Droplet Dysregulation in Alzheimer’s Disease and Neuropsychiatric Disorders

Contact Info

Product

Resources

About