Importance of glutamine in synaptic vesicles revealed by functional studies of SLC6A17 and its mutations pathogenic for intellectual disability
Human mutations in the gene encoding the solute carrier (SLC) 6A17 caused intellectual disability (ID). The physiological role of SLC6A17 and pathogenesis of SLC6A17-based-ID were both unclear. Here, we report learning deficits in Slc6a17 knockout and point mutant mice. Biochemistry, proteomic, and...
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| Format: | Article |
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eLife Sciences Publications Ltd
2023-07-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/86972 |
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| author | Xiaobo Jia Jiemin Zhu Xiling Bian Sulin Liu Sihan Yu Wenjun Liang Lifen Jiang Renbo Mao Wenxia Zhang Yi Rao |
| author_facet | Xiaobo Jia Jiemin Zhu Xiling Bian Sulin Liu Sihan Yu Wenjun Liang Lifen Jiang Renbo Mao Wenxia Zhang Yi Rao |
| author_sort | Xiaobo Jia |
| collection | DOAJ |
| description | Human mutations in the gene encoding the solute carrier (SLC) 6A17 caused intellectual disability (ID). The physiological role of SLC6A17 and pathogenesis of SLC6A17-based-ID were both unclear. Here, we report learning deficits in Slc6a17 knockout and point mutant mice. Biochemistry, proteomic, and electron microscopy (EM) support SLC6A17 protein localization in synaptic vesicles (SVs). Chemical analysis of SVs by liquid chromatography coupled to mass spectrometry (LC-MS) revealed glutamine (Gln) in SVs containing SLC6A17. Virally mediated overexpression of SLC6A17 increased Gln in SVs. Either genetic or virally mediated targeting of Slc6a17 reduced Gln in SVs. One ID mutation caused SLC6A17 mislocalization while the other caused defective Gln transport. Multidisciplinary approaches with seven types of genetically modified mice have shown Gln as an endogenous substrate of SLC6A17, uncovered Gln as a new molecule in SVs, established the necessary and sufficient roles of SLC6A17 in Gln transport into SVs, and suggested SV Gln decrease as the key pathogenetic mechanism in human ID. |
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| format | Article |
| id | doaj.art-5c26753b049a44ea8579120302e0fb8b |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-03-12T23:50:14Z |
| publishDate | 2023-07-01 |
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| spelling | doaj.art-5c26753b049a44ea8579120302e0fb8b2023-07-13T16:15:22ZengeLife Sciences Publications LtdeLife2050-084X2023-07-011210.7554/eLife.86972Importance of glutamine in synaptic vesicles revealed by functional studies of SLC6A17 and its mutations pathogenic for intellectual disabilityXiaobo Jia0https://orcid.org/0000-0002-4214-8906Jiemin Zhu1Xiling Bian2Sulin Liu3https://orcid.org/0000-0002-6776-2216Sihan Yu4Wenjun Liang5Lifen Jiang6Renbo Mao7Wenxia Zhang8Yi Rao9https://orcid.org/0000-0002-0405-5426Chinese Institute for Brain Research, Beijing, China; Changping Laboratory, Beijing, China; Research Unit of Medical Neurobiology, Chinese Academy of Medical Sciences, Beijing, ChinaLaboratory of Neurochemical Biology, PKU-IDG/McGovern Institute for Brain Research, Peking-Tsinghua Center for Life Sciences, School of Life Sciences, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, School of Chemistry and Chemical Engineering, Peking University, Beijing, ChinaLaboratory of Neurochemical Biology, PKU-IDG/McGovern Institute for Brain Research, Peking-Tsinghua Center for Life Sciences, School of Life Sciences, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, School of Chemistry and Chemical Engineering, Peking University, Beijing, ChinaChangping Laboratory, Beijing, ChinaChinese Institute for Brain Research, Beijing, ChinaChangping Laboratory, Beijing, ChinaInstitute of Molecular Physiology, Shenzhen Bay Laboratory, Shenzhen, ChinaChinese Institute for Brain Research, Beijing, ChinaLaboratory of Neurochemical Biology, PKU-IDG/McGovern Institute for Brain Research, Peking-Tsinghua Center for Life Sciences, School of Life Sciences, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, School of Chemistry and Chemical Engineering, Peking University, Beijing, ChinaChinese Institute for Brain Research, Beijing, China; Changping Laboratory, Beijing, China; Research Unit of Medical Neurobiology, Chinese Academy of Medical Sciences, Beijing, China; Laboratory of Neurochemical Biology, PKU-IDG/McGovern Institute for Brain Research, Peking-Tsinghua Center for Life Sciences, School of Life Sciences, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, School of Chemistry and Chemical Engineering, Peking University, Beijing, China; Institute of Molecular Physiology, Shenzhen Bay Laboratory, Shenzhen, China; Capital Medical University, Beijing, ChinaHuman mutations in the gene encoding the solute carrier (SLC) 6A17 caused intellectual disability (ID). The physiological role of SLC6A17 and pathogenesis of SLC6A17-based-ID were both unclear. Here, we report learning deficits in Slc6a17 knockout and point mutant mice. Biochemistry, proteomic, and electron microscopy (EM) support SLC6A17 protein localization in synaptic vesicles (SVs). Chemical analysis of SVs by liquid chromatography coupled to mass spectrometry (LC-MS) revealed glutamine (Gln) in SVs containing SLC6A17. Virally mediated overexpression of SLC6A17 increased Gln in SVs. Either genetic or virally mediated targeting of Slc6a17 reduced Gln in SVs. One ID mutation caused SLC6A17 mislocalization while the other caused defective Gln transport. Multidisciplinary approaches with seven types of genetically modified mice have shown Gln as an endogenous substrate of SLC6A17, uncovered Gln as a new molecule in SVs, established the necessary and sufficient roles of SLC6A17 in Gln transport into SVs, and suggested SV Gln decrease as the key pathogenetic mechanism in human ID.https://elifesciences.org/articles/86972SLC6A17learningmemoryglutaminesynaptic vesicle |
| spellingShingle | Xiaobo Jia Jiemin Zhu Xiling Bian Sulin Liu Sihan Yu Wenjun Liang Lifen Jiang Renbo Mao Wenxia Zhang Yi Rao Importance of glutamine in synaptic vesicles revealed by functional studies of SLC6A17 and its mutations pathogenic for intellectual disability eLife SLC6A17 learning memory glutamine synaptic vesicle |
| title | Importance of glutamine in synaptic vesicles revealed by functional studies of SLC6A17 and its mutations pathogenic for intellectual disability |
| title_full | Importance of glutamine in synaptic vesicles revealed by functional studies of SLC6A17 and its mutations pathogenic for intellectual disability |
| title_fullStr | Importance of glutamine in synaptic vesicles revealed by functional studies of SLC6A17 and its mutations pathogenic for intellectual disability |
| title_full_unstemmed | Importance of glutamine in synaptic vesicles revealed by functional studies of SLC6A17 and its mutations pathogenic for intellectual disability |
| title_short | Importance of glutamine in synaptic vesicles revealed by functional studies of SLC6A17 and its mutations pathogenic for intellectual disability |
| title_sort | importance of glutamine in synaptic vesicles revealed by functional studies of slc6a17 and its mutations pathogenic for intellectual disability |
| topic | SLC6A17 learning memory glutamine synaptic vesicle |
| url | https://elifesciences.org/articles/86972 |
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