María Sanchiz-Calvo, Elena Coccia, Christopher Cawthorne, Gustavo Morrone Parfitt, Teresa Torre-Muruzabal, George Tsafaras, Koen Van Laere, Diego Cabezudo, Ana Cascalho, Chris Van den Haute, Peter Vangheluwe, Joel Blanchard, Eduard Bentea, Veerle Baekelandt
{"title":"溶酶体脂质翻转酶ATP10B的缺失导致进行性多巴胺能神经变性和帕金森运动障碍。","authors":"María Sanchiz-Calvo, Elena Coccia, Christopher Cawthorne, Gustavo Morrone Parfitt, Teresa Torre-Muruzabal, George Tsafaras, Koen Van Laere, Diego Cabezudo, Ana Cascalho, Chris Van den Haute, Peter Vangheluwe, Joel Blanchard, Eduard Bentea, Veerle Baekelandt","doi":"10.1007/s00401-025-02908-0","DOIUrl":null,"url":null,"abstract":"<p><p>ATP10B, a transmembrane lipid flippase located in late endosomes and lysosomes, facilitates the export of glucosylceramide and phosphatidylcholine by coupling this process to ATP hydrolysis. Recently, loss-of-function mutations in the ATP10B gene have been identified in Parkinson's disease patients, pointing to ATP10B as a candidate genetic risk factor. Previous studies have shown compromised lysosomal functionality upon ATP10B knockdown in human cell lines and primary cortical neurons. To investigate the role of ATP10B in Parkinson's disease neuropathology, specifically in the nigrostriatal dopaminergic system, we induced ATP10B knockdown specifically in substantia nigra pars compacta neurons of rats using viral vector technology. Additionally, midbrain neuronal cultures derived from ATP10B knock-out human induced pluripotent stem cells clones were used to study the impact of ATP10B loss in dopaminergic neurons in a more translational model. Atp10b knockdown in rat brain induced parkinsonian motor deficits, and longitudinal striatal dopamine transporter <sup>18</sup>F-FE-PE2I PET imaging revealed a progressive decrease in binding potential. Immunohistochemical analysis conducted one year post-injection confirmed the loss of dopaminergic terminals in the striatum, alongside a loss of dopaminergic neurons in the substantia nigra pars compacta. The expression of LAMP1, LAMP2a, cathepsin B and glucocerebrosidase was studied in dopaminergic neurons. A decrease in lysosomal numbers and an increase in lysosomal volume were observed more consistently in one of the knockdown constructs. The vulnerability of dopaminergic neurons to ATP10B loss-of-function was also observed in midbrain neuronal cultures derived from ATP10B knock-out human induced pluripotent stem cells clones, which showed a significant reduction in TH-positive neurons. Taken together, our findings demonstrate that ATP10B depletion detrimentally impacts the viability of dopaminergic neurons both in vivo and in vitro. Moreover, a broader impact on the functionality of the nigrostriatal pathway was evidenced as rats with Atp10b knockdown exhibited motor impairments similar to those observed in Parkinson's disease patients.</p>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"150 1","pages":"5"},"PeriodicalIF":9.3000,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12271281/pdf/","citationCount":"0","resultStr":"{\"title\":\"Loss of the lysosomal lipid flippase ATP10B leads to progressive dopaminergic neurodegeneration and parkinsonian motor deficits.\",\"authors\":\"María Sanchiz-Calvo, Elena Coccia, Christopher Cawthorne, Gustavo Morrone Parfitt, Teresa Torre-Muruzabal, George Tsafaras, Koen Van Laere, Diego Cabezudo, Ana Cascalho, Chris Van den Haute, Peter Vangheluwe, Joel Blanchard, Eduard Bentea, Veerle Baekelandt\",\"doi\":\"10.1007/s00401-025-02908-0\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>ATP10B, a transmembrane lipid flippase located in late endosomes and lysosomes, facilitates the export of glucosylceramide and phosphatidylcholine by coupling this process to ATP hydrolysis. Recently, loss-of-function mutations in the ATP10B gene have been identified in Parkinson's disease patients, pointing to ATP10B as a candidate genetic risk factor. Previous studies have shown compromised lysosomal functionality upon ATP10B knockdown in human cell lines and primary cortical neurons. To investigate the role of ATP10B in Parkinson's disease neuropathology, specifically in the nigrostriatal dopaminergic system, we induced ATP10B knockdown specifically in substantia nigra pars compacta neurons of rats using viral vector technology. Additionally, midbrain neuronal cultures derived from ATP10B knock-out human induced pluripotent stem cells clones were used to study the impact of ATP10B loss in dopaminergic neurons in a more translational model. Atp10b knockdown in rat brain induced parkinsonian motor deficits, and longitudinal striatal dopamine transporter <sup>18</sup>F-FE-PE2I PET imaging revealed a progressive decrease in binding potential. Immunohistochemical analysis conducted one year post-injection confirmed the loss of dopaminergic terminals in the striatum, alongside a loss of dopaminergic neurons in the substantia nigra pars compacta. The expression of LAMP1, LAMP2a, cathepsin B and glucocerebrosidase was studied in dopaminergic neurons. A decrease in lysosomal numbers and an increase in lysosomal volume were observed more consistently in one of the knockdown constructs. The vulnerability of dopaminergic neurons to ATP10B loss-of-function was also observed in midbrain neuronal cultures derived from ATP10B knock-out human induced pluripotent stem cells clones, which showed a significant reduction in TH-positive neurons. Taken together, our findings demonstrate that ATP10B depletion detrimentally impacts the viability of dopaminergic neurons both in vivo and in vitro. Moreover, a broader impact on the functionality of the nigrostriatal pathway was evidenced as rats with Atp10b knockdown exhibited motor impairments similar to those observed in Parkinson's disease patients.</p>\",\"PeriodicalId\":7012,\"journal\":{\"name\":\"Acta Neuropathologica\",\"volume\":\"150 1\",\"pages\":\"5\"},\"PeriodicalIF\":9.3000,\"publicationDate\":\"2025-07-17\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12271281/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Acta Neuropathologica\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1007/s00401-025-02908-0\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Acta Neuropathologica","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s00401-025-02908-0","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
Loss of the lysosomal lipid flippase ATP10B leads to progressive dopaminergic neurodegeneration and parkinsonian motor deficits.
ATP10B, a transmembrane lipid flippase located in late endosomes and lysosomes, facilitates the export of glucosylceramide and phosphatidylcholine by coupling this process to ATP hydrolysis. Recently, loss-of-function mutations in the ATP10B gene have been identified in Parkinson's disease patients, pointing to ATP10B as a candidate genetic risk factor. Previous studies have shown compromised lysosomal functionality upon ATP10B knockdown in human cell lines and primary cortical neurons. To investigate the role of ATP10B in Parkinson's disease neuropathology, specifically in the nigrostriatal dopaminergic system, we induced ATP10B knockdown specifically in substantia nigra pars compacta neurons of rats using viral vector technology. Additionally, midbrain neuronal cultures derived from ATP10B knock-out human induced pluripotent stem cells clones were used to study the impact of ATP10B loss in dopaminergic neurons in a more translational model. Atp10b knockdown in rat brain induced parkinsonian motor deficits, and longitudinal striatal dopamine transporter 18F-FE-PE2I PET imaging revealed a progressive decrease in binding potential. Immunohistochemical analysis conducted one year post-injection confirmed the loss of dopaminergic terminals in the striatum, alongside a loss of dopaminergic neurons in the substantia nigra pars compacta. The expression of LAMP1, LAMP2a, cathepsin B and glucocerebrosidase was studied in dopaminergic neurons. A decrease in lysosomal numbers and an increase in lysosomal volume were observed more consistently in one of the knockdown constructs. The vulnerability of dopaminergic neurons to ATP10B loss-of-function was also observed in midbrain neuronal cultures derived from ATP10B knock-out human induced pluripotent stem cells clones, which showed a significant reduction in TH-positive neurons. Taken together, our findings demonstrate that ATP10B depletion detrimentally impacts the viability of dopaminergic neurons both in vivo and in vitro. Moreover, a broader impact on the functionality of the nigrostriatal pathway was evidenced as rats with Atp10b knockdown exhibited motor impairments similar to those observed in Parkinson's disease patients.
期刊介绍:
Acta Neuropathologica publishes top-quality papers on the pathology of neurological diseases and experimental studies on molecular and cellular mechanisms using in vitro and in vivo models, ideally validated by analysis of human tissues. The journal accepts Original Papers, Review Articles, Case Reports, and Scientific Correspondence (Letters). Manuscripts must adhere to ethical standards, including review by appropriate ethics committees for human studies and compliance with principles of laboratory animal care for animal experiments. Failure to comply may result in rejection of the manuscript, and authors are responsible for ensuring accuracy and adherence to these requirements.