The role of alpha-synuclein in synucleinopathy: Impact on lipid regulation at mitochondria–ER membranes
Abstract The protein alpha-synuclein (αSyn) plays a pivotal role in the pathogenesis of synucleinopathies, including Parkinson’s disease and multiple system atrophy, with growing evidence indicating that lipid dyshomeostasis is a key phenotype in these neurodegenerative disorders. Previously, we ide...
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Nature Portfolio
2025-04-01
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| Series: | npj Parkinson's Disease |
| Online Access: | https://doi.org/10.1038/s41531-025-00960-x |
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| author | Peter A. Barbuti Cristina Guardia-Laguarta Taekyung Yun Zena K. Chatila Xena Flowers Chantel Wong Bruno F. R. Santos Simone B. Larsen James S. Lotti Nobutaka Hattori Elizabeth Bradshaw Ulf Dettmer Saranna Fanning Vilas Menon Hasini Reddy Andrew F. Teich Rejko Krüger Estela Area-Gomez Serge Przedborski |
| author_facet | Peter A. Barbuti Cristina Guardia-Laguarta Taekyung Yun Zena K. Chatila Xena Flowers Chantel Wong Bruno F. R. Santos Simone B. Larsen James S. Lotti Nobutaka Hattori Elizabeth Bradshaw Ulf Dettmer Saranna Fanning Vilas Menon Hasini Reddy Andrew F. Teich Rejko Krüger Estela Area-Gomez Serge Przedborski |
| author_sort | Peter A. Barbuti |
| collection | DOAJ |
| description | Abstract The protein alpha-synuclein (αSyn) plays a pivotal role in the pathogenesis of synucleinopathies, including Parkinson’s disease and multiple system atrophy, with growing evidence indicating that lipid dyshomeostasis is a key phenotype in these neurodegenerative disorders. Previously, we identified that αSyn localizes, at least in part, to mitochondria-associated endoplasmic reticulum membranes (MAMs), which are transient functional domains containing proteins that regulate lipid metabolism, including the de novo synthesis of phosphatidylserine. In the present study, we analyzed the lipid composition of postmortem human samples, focusing on the substantia nigra pars compacta of Parkinson’s disease and controls, as well as three less affected brain regions of Parkinson’s donors. To further assess synucleinopathy-related lipidome alterations, similar analyses were performed on the striatum of multiple system atrophy cases. Our data reveal region- and disease-specific changes in the levels of lipid species. Specifically, our data revealed alterations in the levels of specific phosphatidylserine species in brain areas most affected in Parkinson’s disease. Some of these alterations, albeit to a lesser degree, are also observed in multiple system atrophy. Using induced pluripotent stem cell-derived neurons, we show that αSyn regulates phosphatidylserine metabolism at MAM domains, and that αSyn dosage parallels the perturbation in phosphatidylserine levels. These findings support the notion that αSyn pathophysiology is linked to the dysregulation of lipid homeostasis, which may contribute to the vulnerability of specific brain regions in synucleinopathy. These findings have significant therapeutic implications. |
| format | Article |
| id | doaj-art-5be950d6d2274e6f980d3f866d3e4dca |
| institution | DOAJ |
| issn | 2373-8057 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Parkinson's Disease |
| spelling | doaj-art-5be950d6d2274e6f980d3f866d3e4dca2025-08-20T02:55:25ZengNature Portfolionpj Parkinson's Disease2373-80572025-04-0111111510.1038/s41531-025-00960-xThe role of alpha-synuclein in synucleinopathy: Impact on lipid regulation at mitochondria–ER membranesPeter A. Barbuti0Cristina Guardia-Laguarta1Taekyung Yun2Zena K. Chatila3Xena Flowers4Chantel Wong5Bruno F. R. Santos6Simone B. Larsen7James S. Lotti8Nobutaka Hattori9Elizabeth Bradshaw10Ulf Dettmer11Saranna Fanning12Vilas Menon13Hasini Reddy14Andrew F. Teich15Rejko Krüger16Estela Area-Gomez17Serge Przedborski18Department of Neurology, Columbia University Irving Medical CenterDepartment of Neurology, Columbia University Irving Medical CenterDepartment of Neurology, Columbia University Irving Medical CenterDepartment of Neurology, Columbia University Irving Medical CenterTaub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia UniversityDepartment of Neuroscience, Barnard College of Columbia UniversityTranslational Neuroscience, Luxembourg Centre for Systems Biomedicine, University of LuxembourgTranslational Neuroscience, Luxembourg Centre for Systems Biomedicine, University of LuxembourgAnn Romney Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical SchoolDepartment of Neurology, Juntendo University School of MedicineDepartment of Neurology, Columbia University Irving Medical CenterAnn Romney Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical SchoolAnn Romney Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical SchoolDepartment of Neurology, Columbia University Irving Medical CenterTaub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia UniversityDepartment of Neurology, Columbia University Irving Medical CenterTranslational Neuroscience, Luxembourg Centre for Systems Biomedicine, University of LuxembourgDepartment of Neurology, Columbia University Irving Medical CenterDepartment of Neurology, Columbia University Irving Medical CenterAbstract The protein alpha-synuclein (αSyn) plays a pivotal role in the pathogenesis of synucleinopathies, including Parkinson’s disease and multiple system atrophy, with growing evidence indicating that lipid dyshomeostasis is a key phenotype in these neurodegenerative disorders. Previously, we identified that αSyn localizes, at least in part, to mitochondria-associated endoplasmic reticulum membranes (MAMs), which are transient functional domains containing proteins that regulate lipid metabolism, including the de novo synthesis of phosphatidylserine. In the present study, we analyzed the lipid composition of postmortem human samples, focusing on the substantia nigra pars compacta of Parkinson’s disease and controls, as well as three less affected brain regions of Parkinson’s donors. To further assess synucleinopathy-related lipidome alterations, similar analyses were performed on the striatum of multiple system atrophy cases. Our data reveal region- and disease-specific changes in the levels of lipid species. Specifically, our data revealed alterations in the levels of specific phosphatidylserine species in brain areas most affected in Parkinson’s disease. Some of these alterations, albeit to a lesser degree, are also observed in multiple system atrophy. Using induced pluripotent stem cell-derived neurons, we show that αSyn regulates phosphatidylserine metabolism at MAM domains, and that αSyn dosage parallels the perturbation in phosphatidylserine levels. These findings support the notion that αSyn pathophysiology is linked to the dysregulation of lipid homeostasis, which may contribute to the vulnerability of specific brain regions in synucleinopathy. These findings have significant therapeutic implications.https://doi.org/10.1038/s41531-025-00960-x |
| spellingShingle | Peter A. Barbuti Cristina Guardia-Laguarta Taekyung Yun Zena K. Chatila Xena Flowers Chantel Wong Bruno F. R. Santos Simone B. Larsen James S. Lotti Nobutaka Hattori Elizabeth Bradshaw Ulf Dettmer Saranna Fanning Vilas Menon Hasini Reddy Andrew F. Teich Rejko Krüger Estela Area-Gomez Serge Przedborski The role of alpha-synuclein in synucleinopathy: Impact on lipid regulation at mitochondria–ER membranes npj Parkinson's Disease |
| title | The role of alpha-synuclein in synucleinopathy: Impact on lipid regulation at mitochondria–ER membranes |
| title_full | The role of alpha-synuclein in synucleinopathy: Impact on lipid regulation at mitochondria–ER membranes |
| title_fullStr | The role of alpha-synuclein in synucleinopathy: Impact on lipid regulation at mitochondria–ER membranes |
| title_full_unstemmed | The role of alpha-synuclein in synucleinopathy: Impact on lipid regulation at mitochondria–ER membranes |
| title_short | The role of alpha-synuclein in synucleinopathy: Impact on lipid regulation at mitochondria–ER membranes |
| title_sort | role of alpha synuclein in synucleinopathy impact on lipid regulation at mitochondria er membranes |
| url | https://doi.org/10.1038/s41531-025-00960-x |
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