The cholesterol 24-hydroxylase CYP46A1 promotes α-synuclein pathology in Parkinson's disease.
Parkinson's disease (PD) is a neurodegenerative disease characterized by the death of dopaminergic neurons in the substantia nigra and the formation of Lewy bodies that are composed of aggregated α-synuclein (α-Syn). However, the factors that regulate α-Syn pathology and nigrostriatal dopaminer...
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Public Library of Science (PLoS)
2025-02-01
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| Series: | PLoS Biology |
| Online Access: | https://doi.org/10.1371/journal.pbio.3002974 |
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| author | Lijun Dai Jiannan Wang Lanxia Meng Xingyu Zhang Tingting Xiao Min Deng Guiqin Chen Jing Xiong Wei Ke Zhengyuan Hong Lihong Bu Zhentao Zhang |
| author_facet | Lijun Dai Jiannan Wang Lanxia Meng Xingyu Zhang Tingting Xiao Min Deng Guiqin Chen Jing Xiong Wei Ke Zhengyuan Hong Lihong Bu Zhentao Zhang |
| author_sort | Lijun Dai |
| collection | DOAJ |
| description | Parkinson's disease (PD) is a neurodegenerative disease characterized by the death of dopaminergic neurons in the substantia nigra and the formation of Lewy bodies that are composed of aggregated α-synuclein (α-Syn). However, the factors that regulate α-Syn pathology and nigrostriatal dopaminergic degeneration remain poorly understood. Previous studies demonstrate cholesterol 24-hydroxylase (CYP46A1) increases the risk for PD. Moreover, 24-hydroxycholesterol (24-OHC), a brain-specific oxysterol that is catalyzed by CYP46A1, is elevated in the cerebrospinal fluid of PD patients. Herein, we show that the levels of CYP46A1 and 24-OHC are elevated in PD patients and increase with age in a mouse model. Overexpression of CYP46A1 intensifies α-Syn pathology, whereas genetic removal of CYP46A1 attenuates α-Syn neurotoxicity and nigrostriatal dopaminergic degeneration in the brain. Moreover, supplementation with exogenous 24-OHC exacerbates the mitochondrial dysfunction induced by α-Syn fibrils. Intracerebral injection of 24-OHC enhances the spread of α-Syn pathology and dopaminergic neurodegeneration via elevated X-box binding protein 1 (XBP1) and lymphocyte-activation gene 3 (LAG3) levels. Thus, elevated CYP46A1 and 24-OHC promote neurotoxicity and the spread of α-Syn via the XBP1-LAG3 axis. Strategies aimed at inhibiting the CYP46A1-24-OHC axis and LAG3 could hold promise as disease-modifying therapies for PD. |
| format | Article |
| id | doaj-art-1247bfa1203a40e9be44ded2aad45b88 |
| institution | DOAJ |
| issn | 1544-9173 1545-7885 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Biology |
| spelling | doaj-art-1247bfa1203a40e9be44ded2aad45b882025-08-20T02:56:20ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852025-02-01232e300297410.1371/journal.pbio.3002974The cholesterol 24-hydroxylase CYP46A1 promotes α-synuclein pathology in Parkinson's disease.Lijun DaiJiannan WangLanxia MengXingyu ZhangTingting XiaoMin DengGuiqin ChenJing XiongWei KeZhengyuan HongLihong BuZhentao ZhangParkinson's disease (PD) is a neurodegenerative disease characterized by the death of dopaminergic neurons in the substantia nigra and the formation of Lewy bodies that are composed of aggregated α-synuclein (α-Syn). However, the factors that regulate α-Syn pathology and nigrostriatal dopaminergic degeneration remain poorly understood. Previous studies demonstrate cholesterol 24-hydroxylase (CYP46A1) increases the risk for PD. Moreover, 24-hydroxycholesterol (24-OHC), a brain-specific oxysterol that is catalyzed by CYP46A1, is elevated in the cerebrospinal fluid of PD patients. Herein, we show that the levels of CYP46A1 and 24-OHC are elevated in PD patients and increase with age in a mouse model. Overexpression of CYP46A1 intensifies α-Syn pathology, whereas genetic removal of CYP46A1 attenuates α-Syn neurotoxicity and nigrostriatal dopaminergic degeneration in the brain. Moreover, supplementation with exogenous 24-OHC exacerbates the mitochondrial dysfunction induced by α-Syn fibrils. Intracerebral injection of 24-OHC enhances the spread of α-Syn pathology and dopaminergic neurodegeneration via elevated X-box binding protein 1 (XBP1) and lymphocyte-activation gene 3 (LAG3) levels. Thus, elevated CYP46A1 and 24-OHC promote neurotoxicity and the spread of α-Syn via the XBP1-LAG3 axis. Strategies aimed at inhibiting the CYP46A1-24-OHC axis and LAG3 could hold promise as disease-modifying therapies for PD.https://doi.org/10.1371/journal.pbio.3002974 |
| spellingShingle | Lijun Dai Jiannan Wang Lanxia Meng Xingyu Zhang Tingting Xiao Min Deng Guiqin Chen Jing Xiong Wei Ke Zhengyuan Hong Lihong Bu Zhentao Zhang The cholesterol 24-hydroxylase CYP46A1 promotes α-synuclein pathology in Parkinson's disease. PLoS Biology |
| title | The cholesterol 24-hydroxylase CYP46A1 promotes α-synuclein pathology in Parkinson's disease. |
| title_full | The cholesterol 24-hydroxylase CYP46A1 promotes α-synuclein pathology in Parkinson's disease. |
| title_fullStr | The cholesterol 24-hydroxylase CYP46A1 promotes α-synuclein pathology in Parkinson's disease. |
| title_full_unstemmed | The cholesterol 24-hydroxylase CYP46A1 promotes α-synuclein pathology in Parkinson's disease. |
| title_short | The cholesterol 24-hydroxylase CYP46A1 promotes α-synuclein pathology in Parkinson's disease. |
| title_sort | cholesterol 24 hydroxylase cyp46a1 promotes α synuclein pathology in parkinson s disease |
| url | https://doi.org/10.1371/journal.pbio.3002974 |
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