Loss of function of OTUD7A in the schizophrenia- associated 15q13.3 deletion impairs synapse development and function in human neurons

Kozlova, Alena; Zhang, Siwei; Kotlar, Alex V.; Jamison, Brendan; Zhang, Hanwen; Shi, Serena; Forrest, Marc P.; McDaid, John; Cutler, David J.; Epstein, Michael P.; Zwick, Michael E.; Pang, Zhiping P.; Sanders, Alan R.; Warren, Stephen T.; Gejman, Pablo V.; Mullé, Jennifer G.; Duan, Jubao

doi:10.1016/j.ajhg.2022.07.001

Cited by 12 publications

(4 citation statements)

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“…The recent study by Unda et al [1] for the first time identified the interaction between OTUD7A and Ankyrins which regulate important aspects of dendritic spine and axon initial segment (AIS) formation. While impaired dendritic branching and spines formation in cortical neurons of Df(h15q13)/+ mice have been previously described, in this paper they provide cross-species evidence for a role of OTUD7A in this phenotype [4][5][6]. They found that the heterozygous 15q13.3 microdeletion in both mouse and iPSC-derived neuronal (iNeuron) models lead to decreased dendritic arborization of cortical neurons.…”

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The OTUD7A-Ankyrin pathway: a newly identified disease mechanism for the 15q13.3 microdeletion disorder

et al. 2023

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The following full text is a publisher's version.For additional information about this publication click this link. https://repository.ubn.ru.nl/handle/2066/293597Please be advised that this information was generated on 2024-06-03 and may be subject to change. Article 25fa End User AgreementThis publication is distributed under the terms of Article 25fa of the Dutch Copyright Act. This article entitles the maker of a short scientific work funded either wholly or partially by Dutch public funds to make that work publicly available for no consideration following a reasonable period of time after the work was first published, provided that clear reference is made to the source of the first publication of the work.Research outputs of researchers employed by Dutch Universities that comply with the legal requirements of Article 25fa of the Dutch Copyright Act, are distributed online and free of cost or other barriers in institutional repositories. Research outputs are distributed six months after their first online publication in the original published version and with proper attribution to the source of the original publication.

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“…It would be interesting to measure OTUD7A expression in neurons derived from patients with small 15q13.3 microdeletions. Finally, while the expression of OTUD7A is higher in excitatory neurons, it might be worthwhile to investigate the role of OTUD7A in other cell types [5].…”

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confidence: 99%

The OTUD7A-Ankyrin pathway: a newly identified disease mechanism for the 15q13.3 microdeletion disorder

et al. 2023

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“…In the case of 22q11.2 deletion, the use of such models has allowed the identification of trans effects of this deletion during the process of neuronal differentiation with a large effect on genes previously identified in SZ GWAS, as for example MEF2C (Myocyte-specific enhancer factor 2C) (Nehme et al 2022). A similar approach based on the 15q13.3 deletion identified a SZ-associated loss of function genetic variant in the OTUD7A gene (OTU domain-containing protein 7A), mapping to this region, that led to impaired synapse development in IPSC-derived excitatory neurons (Kozlova et al 2022).…”

Section: Induced Pluripotent Stem Cell (Ipsc) Modellingmentioning

confidence: 97%

Neurodevelopmental disturbances in schizophrenia: evidence from genetic and environmental factors

2022

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Since more than 3 decades, schizophrenia (SZ) has been regarded as a neurodevelopmental disorder. The neurodevelopmental hypothesis proposes that SZ is associated with genetic and environmental risk factors, which influence connectivity in neuronal circuits during vulnerable developmental periods. We carried out a non-systematic review of genetic/environmental factors that increase SZ risk in light of its neurodevelopmental hypothesis. We also reviewed the potential impact of SZ-related environmental and genetic risk factors on grey and white matter pathology and brain function based on magnetic resonance imaging and post-mortem studies. Finally, we reviewed studies that have used patient-derived neuronal models to gain knowledge of the role of genetic and environmental factors in early developmental stages. Taken together, these studies indicate that a variety of environmental factors may interact with genetic risk factors during the pre- or postnatal period and/or during adolescence to induce symptoms of SZ in early adulthood. These risk factors induce disturbances of macro- and microconnectivity in brain regions involving the prefrontal, temporal and parietal cortices and the hippocampus. On the molecular and cellular level, a disturbed synaptic plasticity, loss of oligodendrocytes and impaired myelination have been shown in brain regions of SZ patients. These cellular/histological phenotypes are related to environmental risk factors such as obstetric complications, maternal infections and childhood trauma and genetic risk factors identified in recent genome-wide association studies. SZ-related genetic risk may contribute to active processes interfering with synaptic plasticity in the adult brain. Advances in stem cell technologies are providing promising mechanistic insights into how SZ risk factors impact the developing brain. Further research is needed to understand the timing of the different complex biological processes taking place as a result of the interplay between genetic and environmental factors.

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“…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

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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.

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Loss of function of OTUD7A in the schizophrenia- associated 15q13.3 deletion impairs synapse development and function in human neurons

Cited by 12 publications

References 100 publications

The OTUD7A-Ankyrin pathway: a newly identified disease mechanism for the 15q13.3 microdeletion disorder

The OTUD7A-Ankyrin pathway: a newly identified disease mechanism for the 15q13.3 microdeletion disorder

Neurodevelopmental disturbances in schizophrenia: evidence from genetic and environmental factors

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

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