GABAAR-PPT1 palmitoylation homeostasis controls synaptic transmission and circuitry oscillation
Abstract The infantile neuronal ceroid lipofuscinosis, also called CLN1 disease, is a fatal neurodegenerative disease caused by mutations in the CLN1 gene encoding palmitoyl protein thioesterase 1 (PPT1). Identifying the depalmitoylation substrates of PPT1 is crucial for understanding CLN1 disease....
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2024-12-01
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| Series: | Translational Psychiatry |
| Online Access: | https://doi.org/10.1038/s41398-024-03206-1 |
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| author | Jia Tong Jingjing Gao Yawei Qi Ziyan Gao Qianqian Wang Yang Liu Tiangang Yuan Minglong Ren Guixia Yang Zhaoyue Li Jin Li Hongyuan Sun Xing Zhao Yeung-Yeung Leung Yonghui Mu Jiamin Xu Chengbiao Lu Shiyong Peng Lihao Ge |
| author_facet | Jia Tong Jingjing Gao Yawei Qi Ziyan Gao Qianqian Wang Yang Liu Tiangang Yuan Minglong Ren Guixia Yang Zhaoyue Li Jin Li Hongyuan Sun Xing Zhao Yeung-Yeung Leung Yonghui Mu Jiamin Xu Chengbiao Lu Shiyong Peng Lihao Ge |
| author_sort | Jia Tong |
| collection | DOAJ |
| description | Abstract The infantile neuronal ceroid lipofuscinosis, also called CLN1 disease, is a fatal neurodegenerative disease caused by mutations in the CLN1 gene encoding palmitoyl protein thioesterase 1 (PPT1). Identifying the depalmitoylation substrates of PPT1 is crucial for understanding CLN1 disease. In this study, we found that GABAAR, the critical synaptic protein essential for inhibitory neurotransmission, is a substrate of PPT1. PPT1 depalmitoylates GABAAR α1 subunit at Cystein-260, while binding to Cystein-165 and -179. Mutations of PPT1 or its GABAAR α1 subunit binding site enhanced inhibitory synaptic transmission and strengthened oscillations powers but disrupted phase coupling in CA1 region and impaired learning and memory in 1- to 2-months-old PPT1-deficient and Gabra1 em1 mice. Our study highlights the critical role of PPT1 in maintaining GABAAR palmitoylation homeostasis and reveals a previously unknown molecular pathway in CLN1 diseases induced by PPT1 mutations. |
| format | Article |
| id | doaj-art-3d797fa79f4d4542ac061caddaa73d0a |
| institution | Kabale University |
| issn | 2158-3188 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Translational Psychiatry |
| spelling | doaj-art-3d797fa79f4d4542ac061caddaa73d0a2024-12-22T12:49:26ZengNature Publishing GroupTranslational Psychiatry2158-31882024-12-0114111210.1038/s41398-024-03206-1GABAAR-PPT1 palmitoylation homeostasis controls synaptic transmission and circuitry oscillationJia Tong0Jingjing Gao1Yawei Qi2Ziyan Gao3Qianqian Wang4Yang Liu5Tiangang Yuan6Minglong Ren7Guixia Yang8Zhaoyue Li9Jin Li10Hongyuan Sun11Xing Zhao12Yeung-Yeung Leung13Yonghui Mu14Jiamin Xu15Chengbiao Lu16Shiyong Peng17Lihao Ge18The Third Affiliated Hospital of Xinxiang Medical UniversityInstitute of Psychiatry and Neuroscience, Xinxiang Medical UniversityInstitute of Psychiatry and Neuroscience, Xinxiang Medical UniversityInstitute of Psychiatry and Neuroscience, Xinxiang Medical UniversityInstitute of Psychiatry and Neuroscience, Xinxiang Medical UniversityInstitute of Psychiatry and Neuroscience, Xinxiang Medical UniversityInstitute of Psychiatry and Neuroscience, Xinxiang Medical UniversityInstitute of Brain Functional Genomics, East China Normal UniversityInstitute of Psychiatry and Neuroscience, Xinxiang Medical UniversityInstitute of Psychiatry and Neuroscience, Xinxiang Medical UniversityInstitute of Psychiatry and Neuroscience, Xinxiang Medical UniversityInstitute of Psychiatry and Neuroscience, Xinxiang Medical UniversityInstitute of Psychiatry and Neuroscience, Xinxiang Medical UniversityDivision of Brain Sciences, Imperial College Faculty of Medicine, Du Cane RoadBasic Medical College, Xinxiang Medical UniversityInstitute of Brain Functional Genomics, East China Normal UniversityInstitute of Psychiatry and Neuroscience, Xinxiang Medical UniversityInstitute of Psychiatry and Neuroscience, Xinxiang Medical UniversityThe Third Affiliated Hospital of Xinxiang Medical UniversityAbstract The infantile neuronal ceroid lipofuscinosis, also called CLN1 disease, is a fatal neurodegenerative disease caused by mutations in the CLN1 gene encoding palmitoyl protein thioesterase 1 (PPT1). Identifying the depalmitoylation substrates of PPT1 is crucial for understanding CLN1 disease. In this study, we found that GABAAR, the critical synaptic protein essential for inhibitory neurotransmission, is a substrate of PPT1. PPT1 depalmitoylates GABAAR α1 subunit at Cystein-260, while binding to Cystein-165 and -179. Mutations of PPT1 or its GABAAR α1 subunit binding site enhanced inhibitory synaptic transmission and strengthened oscillations powers but disrupted phase coupling in CA1 region and impaired learning and memory in 1- to 2-months-old PPT1-deficient and Gabra1 em1 mice. Our study highlights the critical role of PPT1 in maintaining GABAAR palmitoylation homeostasis and reveals a previously unknown molecular pathway in CLN1 diseases induced by PPT1 mutations.https://doi.org/10.1038/s41398-024-03206-1 |
| spellingShingle | Jia Tong Jingjing Gao Yawei Qi Ziyan Gao Qianqian Wang Yang Liu Tiangang Yuan Minglong Ren Guixia Yang Zhaoyue Li Jin Li Hongyuan Sun Xing Zhao Yeung-Yeung Leung Yonghui Mu Jiamin Xu Chengbiao Lu Shiyong Peng Lihao Ge GABAAR-PPT1 palmitoylation homeostasis controls synaptic transmission and circuitry oscillation Translational Psychiatry |
| title | GABAAR-PPT1 palmitoylation homeostasis controls synaptic transmission and circuitry oscillation |
| title_full | GABAAR-PPT1 palmitoylation homeostasis controls synaptic transmission and circuitry oscillation |
| title_fullStr | GABAAR-PPT1 palmitoylation homeostasis controls synaptic transmission and circuitry oscillation |
| title_full_unstemmed | GABAAR-PPT1 palmitoylation homeostasis controls synaptic transmission and circuitry oscillation |
| title_short | GABAAR-PPT1 palmitoylation homeostasis controls synaptic transmission and circuitry oscillation |
| title_sort | gabaar ppt1 palmitoylation homeostasis controls synaptic transmission and circuitry oscillation |
| url | https://doi.org/10.1038/s41398-024-03206-1 |
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