Impaired neural stress resistance and loss of REST in bipolar disorder
Neurodevelopmental changes and impaired stress resistance have been implicated in the pathogenesis of bipolar disorder (BD), but the underlying regulatory mechanisms are unresolved. Here we describe a human cerebral organoid model of BD that exhibits altered neural development, elevated neural netwo...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
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Springer Nature
2023
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| _version_ | 1811137975826776064 |
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| author | Meyer, Katharina Ling, King-Hwa Yeo, Pei-Ling Spathopoulou, Angeliki Drake, Derek Choi, Jaejoon Aron, Liviu Garcia-Corral, Mariana Ko, Tak Lee, Eunjung Alice Tam, Jenny M. Perlis, Roy H. Church, George M. Tsai, Li-Huei Yankner, Bruce A. |
| author_facet | Meyer, Katharina Ling, King-Hwa Yeo, Pei-Ling Spathopoulou, Angeliki Drake, Derek Choi, Jaejoon Aron, Liviu Garcia-Corral, Mariana Ko, Tak Lee, Eunjung Alice Tam, Jenny M. Perlis, Roy H. Church, George M. Tsai, Li-Huei Yankner, Bruce A. |
| author_sort | Meyer, Katharina |
| collection | UPM |
| description | Neurodevelopmental changes and impaired stress resistance have been implicated in the pathogenesis of bipolar disorder (BD), but the underlying regulatory mechanisms are unresolved. Here we describe a human cerebral organoid model of BD that exhibits altered neural development, elevated neural network activity, and a major shift in the transcriptome. These phenotypic changes were reproduced in cerebral organoids generated from iPS cell lines derived in different laboratories. The BD cerebral organoid transcriptome showed highly significant enrichment for gene targets of the transcriptional repressor REST. This was associated with reduced nuclear REST and REST binding to target gene recognition sites. Reducing the oxygen concentration in organoid cultures to a physiological range ameliorated the developmental phenotype and restored REST expression. These effects were mimicked by treatment with lithium. Reduced nuclear REST and derepression of REST targets genes were also observed in the prefrontal cortex of BD patients. Thus, an impaired cellular stress response in BD cerebral organoids leads to altered neural development and transcriptional dysregulation associated with downregulation of REST. These findings provide a new model and conceptual framework for exploring the molecular basis of BD. |
| first_indexed | 2024-09-25T03:42:50Z |
| format | Article |
| id | upm.eprints-110232 |
| institution | Universiti Putra Malaysia |
| last_indexed | 2024-09-25T03:42:50Z |
| publishDate | 2023 |
| publisher | Springer Nature |
| record_format | dspace |
| spelling | upm.eprints-1102322024-07-05T07:50:56Z http://psasir.upm.edu.my/id/eprint/110232/ Impaired neural stress resistance and loss of REST in bipolar disorder Meyer, Katharina Ling, King-Hwa Yeo, Pei-Ling Spathopoulou, Angeliki Drake, Derek Choi, Jaejoon Aron, Liviu Garcia-Corral, Mariana Ko, Tak Lee, Eunjung Alice Tam, Jenny M. Perlis, Roy H. Church, George M. Tsai, Li-Huei Yankner, Bruce A. Neurodevelopmental changes and impaired stress resistance have been implicated in the pathogenesis of bipolar disorder (BD), but the underlying regulatory mechanisms are unresolved. Here we describe a human cerebral organoid model of BD that exhibits altered neural development, elevated neural network activity, and a major shift in the transcriptome. These phenotypic changes were reproduced in cerebral organoids generated from iPS cell lines derived in different laboratories. The BD cerebral organoid transcriptome showed highly significant enrichment for gene targets of the transcriptional repressor REST. This was associated with reduced nuclear REST and REST binding to target gene recognition sites. Reducing the oxygen concentration in organoid cultures to a physiological range ameliorated the developmental phenotype and restored REST expression. These effects were mimicked by treatment with lithium. Reduced nuclear REST and derepression of REST targets genes were also observed in the prefrontal cortex of BD patients. Thus, an impaired cellular stress response in BD cerebral organoids leads to altered neural development and transcriptional dysregulation associated with downregulation of REST. These findings provide a new model and conceptual framework for exploring the molecular basis of BD. Springer Nature 2023 Article PeerReviewed Meyer, Katharina and Ling, King-Hwa and Yeo, Pei-Ling and Spathopoulou, Angeliki and Drake, Derek and Choi, Jaejoon and Aron, Liviu and Garcia-Corral, Mariana and Ko, Tak and Lee, Eunjung Alice and Tam, Jenny M. and Perlis, Roy H. and Church, George M. and Tsai, Li-Huei and Yankner, Bruce A. (2023) Impaired neural stress resistance and loss of REST in bipolar disorder. Molecular Psychiatry, 29. pp. 153-164. ISSN 1359-4184; ESSN: 1476-5578 https://www.nature.com/articles/s41380-023-02313-7 10.1038/s41380-023-02313-7 |
| spellingShingle | Meyer, Katharina Ling, King-Hwa Yeo, Pei-Ling Spathopoulou, Angeliki Drake, Derek Choi, Jaejoon Aron, Liviu Garcia-Corral, Mariana Ko, Tak Lee, Eunjung Alice Tam, Jenny M. Perlis, Roy H. Church, George M. Tsai, Li-Huei Yankner, Bruce A. Impaired neural stress resistance and loss of REST in bipolar disorder |
| title | Impaired neural stress resistance and loss of REST in bipolar disorder |
| title_full | Impaired neural stress resistance and loss of REST in bipolar disorder |
| title_fullStr | Impaired neural stress resistance and loss of REST in bipolar disorder |
| title_full_unstemmed | Impaired neural stress resistance and loss of REST in bipolar disorder |
| title_short | Impaired neural stress resistance and loss of REST in bipolar disorder |
| title_sort | impaired neural stress resistance and loss of rest in bipolar disorder |
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