A protective role of ABCA5 in response to elevated sphingomyelin levels in Parkinson’s disease
Abstract Parkinson’s disease (PD) is a chronic neurodegenerative disorder that affects the motor system. Increasing evidence indicates that lysosomal dysfunction is pivotal in the pathogenesis of PD, typically characterized by dysregulation of sphingolipids in lysosomes. ATP-binding cassette subfami...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2024-01-01
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| Series: | npj Parkinson's Disease |
| Online Access: | https://doi.org/10.1038/s41531-024-00632-2 |
| _version_ | 1797355902080122880 |
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| author | YuHong Fu Russell Pickford Jasmin Galper Katherine Phan Ping Wu Hongyun Li Young-Bum Kim Nicolas Dzamko Glenda M. Halliday Woojin Scott Kim |
| author_facet | YuHong Fu Russell Pickford Jasmin Galper Katherine Phan Ping Wu Hongyun Li Young-Bum Kim Nicolas Dzamko Glenda M. Halliday Woojin Scott Kim |
| author_sort | YuHong Fu |
| collection | DOAJ |
| description | Abstract Parkinson’s disease (PD) is a chronic neurodegenerative disorder that affects the motor system. Increasing evidence indicates that lysosomal dysfunction is pivotal in the pathogenesis of PD, typically characterized by dysregulation of sphingolipids in lysosomes. ATP-binding cassette subfamily A member 5 (ABCA5) is a lysosomal transporter that mediates the removal of excess sphingomyelin from lysosomes. We therefore investigated whether the expression levels of ABCA5 are associated with sphingomyelin levels and α-synuclein pathology in PD. Firstly, we undertook a comprehensive assessment of the six sphingolipid classes that are part of the lysosomal salvage pathway in the disease-affected amygdala and disease-unaffected visual cortex using liquid chromatography-mass spectrometry. We found that sphingomyelin levels were significantly increased in PD compared to controls and correlated with disease duration only in the amygdala, whereas, the five other sphingolipid classes were slightly altered or unaltered. Concomitantly, the expression of ABCA5 was upregulated in the PD amygdala compared to controls and correlated strongly with sphingomyelin levels. Using neuronal cells, we further verified that the expression of ABCA5 was dependent on cellular levels of sphingomyelin. Interestingly, sphingomyelin levels were strongly associated with α-synuclein in the amygdala and were related to α-synuclein expression. Finally, we revealed that sphingomyelin levels were also increased in PD plasma compared to controls, and that five identical sphingomyelin species were increased in both the brain and the plasma. When put together, these results suggest that in regions accumulating α-synuclein in PD, ABCA5 is upregulated to reduce lysosomal sphingomyelin levels potentially as a protective measure. This process may provide new targets for therapeutic intervention and biomarker development for PD. |
| first_indexed | 2024-03-08T14:17:52Z |
| format | Article |
| id | doaj.art-1335d4aa80e64a35950b58bddbe1e4a0 |
| institution | Directory Open Access Journal |
| issn | 2373-8057 |
| language | English |
| last_indexed | 2024-03-08T14:17:52Z |
| publishDate | 2024-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Parkinson's Disease |
| spelling | doaj.art-1335d4aa80e64a35950b58bddbe1e4a02024-01-14T12:16:13ZengNature Portfolionpj Parkinson's Disease2373-80572024-01-0110111210.1038/s41531-024-00632-2A protective role of ABCA5 in response to elevated sphingomyelin levels in Parkinson’s diseaseYuHong Fu0Russell Pickford1Jasmin Galper2Katherine Phan3Ping Wu4Hongyun Li5Young-Bum Kim6Nicolas Dzamko7Glenda M. Halliday8Woojin Scott Kim9Brain and Mind Centre, The University of SydneyBioanalytical Mass Spectrometry Facility, University of New South WalesBrain and Mind Centre, The University of SydneyBrain and Mind Centre, The University of SydneyBrain and Mind Centre, The University of SydneyBrain and Mind Centre, The University of SydneyDivision of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical SchoolBrain and Mind Centre, The University of SydneyBrain and Mind Centre, The University of SydneyBrain and Mind Centre, The University of SydneyAbstract Parkinson’s disease (PD) is a chronic neurodegenerative disorder that affects the motor system. Increasing evidence indicates that lysosomal dysfunction is pivotal in the pathogenesis of PD, typically characterized by dysregulation of sphingolipids in lysosomes. ATP-binding cassette subfamily A member 5 (ABCA5) is a lysosomal transporter that mediates the removal of excess sphingomyelin from lysosomes. We therefore investigated whether the expression levels of ABCA5 are associated with sphingomyelin levels and α-synuclein pathology in PD. Firstly, we undertook a comprehensive assessment of the six sphingolipid classes that are part of the lysosomal salvage pathway in the disease-affected amygdala and disease-unaffected visual cortex using liquid chromatography-mass spectrometry. We found that sphingomyelin levels were significantly increased in PD compared to controls and correlated with disease duration only in the amygdala, whereas, the five other sphingolipid classes were slightly altered or unaltered. Concomitantly, the expression of ABCA5 was upregulated in the PD amygdala compared to controls and correlated strongly with sphingomyelin levels. Using neuronal cells, we further verified that the expression of ABCA5 was dependent on cellular levels of sphingomyelin. Interestingly, sphingomyelin levels were strongly associated with α-synuclein in the amygdala and were related to α-synuclein expression. Finally, we revealed that sphingomyelin levels were also increased in PD plasma compared to controls, and that five identical sphingomyelin species were increased in both the brain and the plasma. When put together, these results suggest that in regions accumulating α-synuclein in PD, ABCA5 is upregulated to reduce lysosomal sphingomyelin levels potentially as a protective measure. This process may provide new targets for therapeutic intervention and biomarker development for PD.https://doi.org/10.1038/s41531-024-00632-2 |
| spellingShingle | YuHong Fu Russell Pickford Jasmin Galper Katherine Phan Ping Wu Hongyun Li Young-Bum Kim Nicolas Dzamko Glenda M. Halliday Woojin Scott Kim A protective role of ABCA5 in response to elevated sphingomyelin levels in Parkinson’s disease npj Parkinson's Disease |
| title | A protective role of ABCA5 in response to elevated sphingomyelin levels in Parkinson’s disease |
| title_full | A protective role of ABCA5 in response to elevated sphingomyelin levels in Parkinson’s disease |
| title_fullStr | A protective role of ABCA5 in response to elevated sphingomyelin levels in Parkinson’s disease |
| title_full_unstemmed | A protective role of ABCA5 in response to elevated sphingomyelin levels in Parkinson’s disease |
| title_short | A protective role of ABCA5 in response to elevated sphingomyelin levels in Parkinson’s disease |
| title_sort | protective role of abca5 in response to elevated sphingomyelin levels in parkinson s disease |
| url | https://doi.org/10.1038/s41531-024-00632-2 |
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