Inhibition of nSMase2 Reduces the Transfer of Oligomeric α-Synuclein Irrespective of Hypoxia
Recently, extracellular vesicles (EVs), such as exosomes, have been proposed to play an influential role in the cell-to-cell spread of neurodegenerative diseases, including the intercellular transmission of α-synuclein (α-syn). However, the regulation of EV biogenesis and its relation to Parkinson’s...
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| Format: | Article |
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Frontiers Media S.A.
2019-08-01
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| Series: | Frontiers in Molecular Neuroscience |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fnmol.2019.00200/full |
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| author | Valerie Sackmann Valerie Sackmann Maitrayee Sardar Sinha Maitrayee Sardar Sinha Christopher Sackmann Christopher Sackmann Livia Civitelli Livia Civitelli Joakim Bergström Anna Ansell-Schultz Anna Ansell-Schultz Martin Hallbeck Martin Hallbeck |
| author_facet | Valerie Sackmann Valerie Sackmann Maitrayee Sardar Sinha Maitrayee Sardar Sinha Christopher Sackmann Christopher Sackmann Livia Civitelli Livia Civitelli Joakim Bergström Anna Ansell-Schultz Anna Ansell-Schultz Martin Hallbeck Martin Hallbeck |
| author_sort | Valerie Sackmann |
| collection | DOAJ |
| description | Recently, extracellular vesicles (EVs), such as exosomes, have been proposed to play an influential role in the cell-to-cell spread of neurodegenerative diseases, including the intercellular transmission of α-synuclein (α-syn). However, the regulation of EV biogenesis and its relation to Parkinson’s disease (PD) is only partially understood. The generation of EVs through the ESCRT-independent pathway depends on the hydrolysis of sphingomyelin by neutral sphingomyelinase 2 (nSMase2) to produce ceramide, which causes the membrane of endosomal multivesicular bodies to bud inward. nSMase2 is sensitive to oxidative stress, a common process in PD brains; however, little is known about the role of sphingomyelin metabolism in the pathogenesis of PD. This is the first study to show that inhibiting nSMase2 decreases the transfer of oligomeric aggregates of α-syn between neuron-like cells. Furthermore, it reduced the accumulation and aggregation of high-molecular-weight α-syn. Hypoxia, as a model of oxidative stress, reduced the levels of nSMase2, but not its enzymatic activity, and significantly altered the lipid composition of cells without affecting EV abundance or the transfer of α-syn. These data show that altering sphingolipids can mitigate the spread of α-syn, even under hypoxic conditions, potentially suppressing PD progression. |
| first_indexed | 2024-12-18T21:37:00Z |
| format | Article |
| id | doaj.art-8d411cee54494594a6bd351a57e07b82 |
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| issn | 1662-5099 |
| language | English |
| last_indexed | 2024-12-18T21:37:00Z |
| publishDate | 2019-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Neuroscience |
| spelling | doaj.art-8d411cee54494594a6bd351a57e07b822022-12-21T20:50:52ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992019-08-011210.3389/fnmol.2019.00200473712Inhibition of nSMase2 Reduces the Transfer of Oligomeric α-Synuclein Irrespective of HypoxiaValerie Sackmann0Valerie Sackmann1Maitrayee Sardar Sinha2Maitrayee Sardar Sinha3Christopher Sackmann4Christopher Sackmann5Livia Civitelli6Livia Civitelli7Joakim Bergström8Anna Ansell-Schultz9Anna Ansell-Schultz10Martin Hallbeck11Martin Hallbeck12Department of Clinical Pathology, Linköping University, Linköping, SwedenDepartment of Clinical and Experimental Medicine, Linköping University, Linköping, SwedenDepartment of Clinical Pathology, Linköping University, Linköping, SwedenDepartment of Clinical and Experimental Medicine, Linköping University, Linköping, SwedenDepartment of Clinical Pathology, Linköping University, Linköping, SwedenDepartment of Clinical and Experimental Medicine, Linköping University, Linköping, SwedenDepartment of Clinical Pathology, Linköping University, Linköping, SwedenDepartment of Clinical and Experimental Medicine, Linköping University, Linköping, SwedenDepartment of Public Health and Caring Sciences, Uppsala University, Uppsala, SwedenDepartment of Clinical Pathology, Linköping University, Linköping, SwedenDepartment of Clinical and Experimental Medicine, Linköping University, Linköping, SwedenDepartment of Clinical Pathology, Linköping University, Linköping, SwedenDepartment of Clinical and Experimental Medicine, Linköping University, Linköping, SwedenRecently, extracellular vesicles (EVs), such as exosomes, have been proposed to play an influential role in the cell-to-cell spread of neurodegenerative diseases, including the intercellular transmission of α-synuclein (α-syn). However, the regulation of EV biogenesis and its relation to Parkinson’s disease (PD) is only partially understood. The generation of EVs through the ESCRT-independent pathway depends on the hydrolysis of sphingomyelin by neutral sphingomyelinase 2 (nSMase2) to produce ceramide, which causes the membrane of endosomal multivesicular bodies to bud inward. nSMase2 is sensitive to oxidative stress, a common process in PD brains; however, little is known about the role of sphingomyelin metabolism in the pathogenesis of PD. This is the first study to show that inhibiting nSMase2 decreases the transfer of oligomeric aggregates of α-syn between neuron-like cells. Furthermore, it reduced the accumulation and aggregation of high-molecular-weight α-syn. Hypoxia, as a model of oxidative stress, reduced the levels of nSMase2, but not its enzymatic activity, and significantly altered the lipid composition of cells without affecting EV abundance or the transfer of α-syn. These data show that altering sphingolipids can mitigate the spread of α-syn, even under hypoxic conditions, potentially suppressing PD progression.https://www.frontiersin.org/article/10.3389/fnmol.2019.00200/fullParkinson’s diseaseextracellular vesiclesneutral sphingomyelinase 2α-synhypoxiacell-to-cell transmission |
| spellingShingle | Valerie Sackmann Valerie Sackmann Maitrayee Sardar Sinha Maitrayee Sardar Sinha Christopher Sackmann Christopher Sackmann Livia Civitelli Livia Civitelli Joakim Bergström Anna Ansell-Schultz Anna Ansell-Schultz Martin Hallbeck Martin Hallbeck Inhibition of nSMase2 Reduces the Transfer of Oligomeric α-Synuclein Irrespective of Hypoxia Frontiers in Molecular Neuroscience Parkinson’s disease extracellular vesicles neutral sphingomyelinase 2 α-syn hypoxia cell-to-cell transmission |
| title | Inhibition of nSMase2 Reduces the Transfer of Oligomeric α-Synuclein Irrespective of Hypoxia |
| title_full | Inhibition of nSMase2 Reduces the Transfer of Oligomeric α-Synuclein Irrespective of Hypoxia |
| title_fullStr | Inhibition of nSMase2 Reduces the Transfer of Oligomeric α-Synuclein Irrespective of Hypoxia |
| title_full_unstemmed | Inhibition of nSMase2 Reduces the Transfer of Oligomeric α-Synuclein Irrespective of Hypoxia |
| title_short | Inhibition of nSMase2 Reduces the Transfer of Oligomeric α-Synuclein Irrespective of Hypoxia |
| title_sort | inhibition of nsmase2 reduces the transfer of oligomeric α synuclein irrespective of hypoxia |
| topic | Parkinson’s disease extracellular vesicles neutral sphingomyelinase 2 α-syn hypoxia cell-to-cell transmission |
| url | https://www.frontiersin.org/article/10.3389/fnmol.2019.00200/full |
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