Seipin deficiency-induced lipid dysregulation leads to hypomyelination-associated cognitive deficits via compromising oligodendrocyte precursor cell differentiation
Seipin is one key mediator of lipid metabolism that is highly expressed in adipose tissues as well as in the brain. Lack of Seipin gene, Bscl2, leads to not only severe lipid metabolic disorders but also cognitive impairments and motor disabilities. Myelin, composed mainly of lipids, facilitates ner...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
| Published: |
2024
|
| Subjects: | |
| Online Access: | https://hdl.handle.net/10356/179802 |
| _version_ | 1826126861602652160 |
|---|---|
| author | Cui, Wenli Yang, Jing Tu, Chuanyun Zhang, Ziting Zhao, Huifang Qiao, Yan Li, Yanqiu Yang, Wulin Lim, Kah-Leong Ma, Quanhong Zhang, Chengwu Lu, Li |
| author2 | Lee Kong Chian School of Medicine (LKCMedicine) |
| author_facet | Lee Kong Chian School of Medicine (LKCMedicine) Cui, Wenli Yang, Jing Tu, Chuanyun Zhang, Ziting Zhao, Huifang Qiao, Yan Li, Yanqiu Yang, Wulin Lim, Kah-Leong Ma, Quanhong Zhang, Chengwu Lu, Li |
| author_sort | Cui, Wenli |
| collection | NTU |
| description | Seipin is one key mediator of lipid metabolism that is highly expressed in adipose tissues as well as in the brain. Lack of Seipin gene, Bscl2, leads to not only severe lipid metabolic disorders but also cognitive impairments and motor disabilities. Myelin, composed mainly of lipids, facilitates nerve transmission and is important for motor coordination and learning. Whether Seipin deficiency-leaded defects in learning and motor coordination is underlined by lipid dysregulation and its consequent myelin abnormalities remains to be elucidated. In the present study, we verified the expression of Seipin in oligodendrocytes (OLs) and their precursors, oligodendrocyte precursor cells (OPCs), and demonstrated that Seipin deficiency compromised OPC differentiation, which led to decreased OL numbers, myelin protein, myelinated fiber proportion and thickness of myelin. Deficiency of Seipin resulted in impaired spatial cognition and motor coordination in mice. Mechanistically, Seipin deficiency suppressed sphingolipid metabolism-related genes in OPCs and caused morphological abnormalities in lipid droplets (LDs), which markedly impeded OPC differentiation. Importantly, rosiglitazone, one agonist of PPAR-gamma, substantially restored phenotypes resulting from Seipin deficiency, such as aberrant LDs, reduced sphingolipids, obstructed OPC differentiation, and neurobehavioral defects. Collectively, the present study elucidated how Seipin deficiency-induced lipid dysregulation leads to neurobehavioral deficits via impairing myelination, which may pave the way for developing novel intervention strategy for treating metabolism-involved neurological disorders. |
| first_indexed | 2024-10-01T06:59:43Z |
| format | Journal Article |
| id | ntu-10356/179802 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T06:59:43Z |
| publishDate | 2024 |
| record_format | dspace |
| spelling | ntu-10356/1798022024-09-01T15:38:02Z Seipin deficiency-induced lipid dysregulation leads to hypomyelination-associated cognitive deficits via compromising oligodendrocyte precursor cell differentiation Cui, Wenli Yang, Jing Tu, Chuanyun Zhang, Ziting Zhao, Huifang Qiao, Yan Li, Yanqiu Yang, Wulin Lim, Kah-Leong Ma, Quanhong Zhang, Chengwu Lu, Li Lee Kong Chian School of Medicine (LKCMedicine) Medicine, Health and Life Sciences Seipin Lipid dysregulation Seipin is one key mediator of lipid metabolism that is highly expressed in adipose tissues as well as in the brain. Lack of Seipin gene, Bscl2, leads to not only severe lipid metabolic disorders but also cognitive impairments and motor disabilities. Myelin, composed mainly of lipids, facilitates nerve transmission and is important for motor coordination and learning. Whether Seipin deficiency-leaded defects in learning and motor coordination is underlined by lipid dysregulation and its consequent myelin abnormalities remains to be elucidated. In the present study, we verified the expression of Seipin in oligodendrocytes (OLs) and their precursors, oligodendrocyte precursor cells (OPCs), and demonstrated that Seipin deficiency compromised OPC differentiation, which led to decreased OL numbers, myelin protein, myelinated fiber proportion and thickness of myelin. Deficiency of Seipin resulted in impaired spatial cognition and motor coordination in mice. Mechanistically, Seipin deficiency suppressed sphingolipid metabolism-related genes in OPCs and caused morphological abnormalities in lipid droplets (LDs), which markedly impeded OPC differentiation. Importantly, rosiglitazone, one agonist of PPAR-gamma, substantially restored phenotypes resulting from Seipin deficiency, such as aberrant LDs, reduced sphingolipids, obstructed OPC differentiation, and neurobehavioral defects. Collectively, the present study elucidated how Seipin deficiency-induced lipid dysregulation leads to neurobehavioral deficits via impairing myelination, which may pave the way for developing novel intervention strategy for treating metabolism-involved neurological disorders. Published version This work was supported by the National Natural Science Foundation of China [82301759]; the Natural Science Foundation of Shanxi Province [20210302123291, 20210302123299, 20210302124561, 202203021211238]; and the International Science and Technology Cooperation Program of Shanxi Province [202104041101026]. 2024-08-26T01:30:23Z 2024-08-26T01:30:23Z 2024 Journal Article Cui, W., Yang, J., Tu, C., Zhang, Z., Zhao, H., Qiao, Y., Li, Y., Yang, W., Lim, K., Ma, Q., Zhang, C. & Lu, L. (2024). Seipin deficiency-induced lipid dysregulation leads to hypomyelination-associated cognitive deficits via compromising oligodendrocyte precursor cell differentiation. Cell Death & Disease, 15(5), 350-. https://dx.doi.org/10.1038/s41419-024-06737-z 2041-4889 https://hdl.handle.net/10356/179802 10.1038/s41419-024-06737-z 38773070 2-s2.0-85193939193 5 15 350 en Cell Death & Disease © 2024 The Author(s). Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creativecommons.org/licenses/by/4.0/. application/pdf |
| spellingShingle | Medicine, Health and Life Sciences Seipin Lipid dysregulation Cui, Wenli Yang, Jing Tu, Chuanyun Zhang, Ziting Zhao, Huifang Qiao, Yan Li, Yanqiu Yang, Wulin Lim, Kah-Leong Ma, Quanhong Zhang, Chengwu Lu, Li Seipin deficiency-induced lipid dysregulation leads to hypomyelination-associated cognitive deficits via compromising oligodendrocyte precursor cell differentiation |
| title | Seipin deficiency-induced lipid dysregulation leads to hypomyelination-associated cognitive deficits via compromising oligodendrocyte precursor cell differentiation |
| title_full | Seipin deficiency-induced lipid dysregulation leads to hypomyelination-associated cognitive deficits via compromising oligodendrocyte precursor cell differentiation |
| title_fullStr | Seipin deficiency-induced lipid dysregulation leads to hypomyelination-associated cognitive deficits via compromising oligodendrocyte precursor cell differentiation |
| title_full_unstemmed | Seipin deficiency-induced lipid dysregulation leads to hypomyelination-associated cognitive deficits via compromising oligodendrocyte precursor cell differentiation |
| title_short | Seipin deficiency-induced lipid dysregulation leads to hypomyelination-associated cognitive deficits via compromising oligodendrocyte precursor cell differentiation |
| title_sort | seipin deficiency induced lipid dysregulation leads to hypomyelination associated cognitive deficits via compromising oligodendrocyte precursor cell differentiation |
| topic | Medicine, Health and Life Sciences Seipin Lipid dysregulation |
| url | https://hdl.handle.net/10356/179802 |
| work_keys_str_mv | AT cuiwenli seipindeficiencyinducedlipiddysregulationleadstohypomyelinationassociatedcognitivedeficitsviacompromisingoligodendrocyteprecursorcelldifferentiation AT yangjing seipindeficiencyinducedlipiddysregulationleadstohypomyelinationassociatedcognitivedeficitsviacompromisingoligodendrocyteprecursorcelldifferentiation AT tuchuanyun seipindeficiencyinducedlipiddysregulationleadstohypomyelinationassociatedcognitivedeficitsviacompromisingoligodendrocyteprecursorcelldifferentiation AT zhangziting seipindeficiencyinducedlipiddysregulationleadstohypomyelinationassociatedcognitivedeficitsviacompromisingoligodendrocyteprecursorcelldifferentiation AT zhaohuifang seipindeficiencyinducedlipiddysregulationleadstohypomyelinationassociatedcognitivedeficitsviacompromisingoligodendrocyteprecursorcelldifferentiation AT qiaoyan seipindeficiencyinducedlipiddysregulationleadstohypomyelinationassociatedcognitivedeficitsviacompromisingoligodendrocyteprecursorcelldifferentiation AT liyanqiu seipindeficiencyinducedlipiddysregulationleadstohypomyelinationassociatedcognitivedeficitsviacompromisingoligodendrocyteprecursorcelldifferentiation AT yangwulin seipindeficiencyinducedlipiddysregulationleadstohypomyelinationassociatedcognitivedeficitsviacompromisingoligodendrocyteprecursorcelldifferentiation AT limkahleong seipindeficiencyinducedlipiddysregulationleadstohypomyelinationassociatedcognitivedeficitsviacompromisingoligodendrocyteprecursorcelldifferentiation AT maquanhong seipindeficiencyinducedlipiddysregulationleadstohypomyelinationassociatedcognitivedeficitsviacompromisingoligodendrocyteprecursorcelldifferentiation AT zhangchengwu seipindeficiencyinducedlipiddysregulationleadstohypomyelinationassociatedcognitivedeficitsviacompromisingoligodendrocyteprecursorcelldifferentiation AT luli seipindeficiencyinducedlipiddysregulationleadstohypomyelinationassociatedcognitivedeficitsviacompromisingoligodendrocyteprecursorcelldifferentiation |