Prosaposin maintains lipid homeostasis in dopamine neurons and counteracts experimental parkinsonism in rodents
Abstract Prosaposin (PSAP) modulates glycosphingolipid metabolism and variants have been linked to Parkinson’s disease (PD). Here, we find altered PSAP levels in the plasma, CSF and post-mortem brain of PD patients. Altered plasma and CSF PSAP levels correlate with PD-related motor impairments. Dopa...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-09-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-41539-5 |
| _version_ | 1797557895573798912 |
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| author | Yachao He Ibrahim Kaya Reza Shariatgorji Johan Lundkvist Lars U. Wahlberg Anna Nilsson Dejan Mamula Jan Kehr Justyna Zareba-Paslawska Henrik Biverstål Karima Chergui Xiaoqun Zhang Per E. Andren Per Svenningsson |
| author_facet | Yachao He Ibrahim Kaya Reza Shariatgorji Johan Lundkvist Lars U. Wahlberg Anna Nilsson Dejan Mamula Jan Kehr Justyna Zareba-Paslawska Henrik Biverstål Karima Chergui Xiaoqun Zhang Per E. Andren Per Svenningsson |
| author_sort | Yachao He |
| collection | DOAJ |
| description | Abstract Prosaposin (PSAP) modulates glycosphingolipid metabolism and variants have been linked to Parkinson’s disease (PD). Here, we find altered PSAP levels in the plasma, CSF and post-mortem brain of PD patients. Altered plasma and CSF PSAP levels correlate with PD-related motor impairments. Dopaminergic PSAP-deficient (cPSAPDAT) mice display hypolocomotion and depression/anxiety-like symptoms with mildly impaired dopaminergic neurotransmission, while serotonergic PSAP-deficient (cPSAPSERT) mice behave normally. Spatial lipidomics revealed an accumulation of highly unsaturated and shortened lipids and reduction of sphingolipids throughout the brains of cPSAPDAT mice. The overexpression of α-synuclein via AAV lead to more severe dopaminergic degeneration and higher p-Ser129 α-synuclein levels in cPSAPDAT mice compared to WT mice. Overexpression of PSAP via AAV and encapsulated cell biodelivery protected against 6-OHDA and α-synuclein toxicity in wild-type rodents. Thus, these findings suggest PSAP may maintain dopaminergic lipid homeostasis, which is dysregulated in PD, and counteract experimental parkinsonism. |
| first_indexed | 2024-03-10T17:23:41Z |
| format | Article |
| id | doaj.art-bbdd1f902a3a439685091307419305e5 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-10T17:23:41Z |
| publishDate | 2023-09-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-bbdd1f902a3a439685091307419305e52023-11-20T10:16:31ZengNature PortfolioNature Communications2041-17232023-09-0114112210.1038/s41467-023-41539-5Prosaposin maintains lipid homeostasis in dopamine neurons and counteracts experimental parkinsonism in rodentsYachao He0Ibrahim Kaya1Reza Shariatgorji2Johan Lundkvist3Lars U. Wahlberg4Anna Nilsson5Dejan Mamula6Jan Kehr7Justyna Zareba-Paslawska8Henrik Biverstål9Karima Chergui10Xiaoqun Zhang11Per E. Andren12Per Svenningsson13Translational Neuropharmacology, Department of Clinical Neuroscience, Karolinska InstitutetDepartment of Pharmaceutical Biosciences, Medical Mass Spectrometry Imaging, Uppsala UniversityDepartment of Pharmaceutical Biosciences, Medical Mass Spectrometry Imaging, Uppsala UniversityDivision of Neurogeriatrics, Department of Neurobiology, Care Science and Society, Karolinska InstitutetDivision of Neurogeriatrics, Department of Neurobiology, Care Science and Society, Karolinska InstitutetDepartment of Pharmaceutical Biosciences, Medical Mass Spectrometry Imaging, Uppsala UniversityTranslational Neuropharmacology, Department of Clinical Neuroscience, Karolinska InstitutetSection of Pharmacological Neurochemistry, Department of Physiology and Pharmacology, Karolinska InstituteTranslational Neuropharmacology, Department of Clinical Neuroscience, Karolinska InstitutetSinfonia Biotherapeutics ABLaboratory of Molecular Neurophysiology, Department of Physiology and Pharmacology, Karolinska InstitutetTranslational Neuropharmacology, Department of Clinical Neuroscience, Karolinska InstitutetDepartment of Pharmaceutical Biosciences, Medical Mass Spectrometry Imaging, Uppsala UniversityTranslational Neuropharmacology, Department of Clinical Neuroscience, Karolinska InstitutetAbstract Prosaposin (PSAP) modulates glycosphingolipid metabolism and variants have been linked to Parkinson’s disease (PD). Here, we find altered PSAP levels in the plasma, CSF and post-mortem brain of PD patients. Altered plasma and CSF PSAP levels correlate with PD-related motor impairments. Dopaminergic PSAP-deficient (cPSAPDAT) mice display hypolocomotion and depression/anxiety-like symptoms with mildly impaired dopaminergic neurotransmission, while serotonergic PSAP-deficient (cPSAPSERT) mice behave normally. Spatial lipidomics revealed an accumulation of highly unsaturated and shortened lipids and reduction of sphingolipids throughout the brains of cPSAPDAT mice. The overexpression of α-synuclein via AAV lead to more severe dopaminergic degeneration and higher p-Ser129 α-synuclein levels in cPSAPDAT mice compared to WT mice. Overexpression of PSAP via AAV and encapsulated cell biodelivery protected against 6-OHDA and α-synuclein toxicity in wild-type rodents. Thus, these findings suggest PSAP may maintain dopaminergic lipid homeostasis, which is dysregulated in PD, and counteract experimental parkinsonism.https://doi.org/10.1038/s41467-023-41539-5 |
| spellingShingle | Yachao He Ibrahim Kaya Reza Shariatgorji Johan Lundkvist Lars U. Wahlberg Anna Nilsson Dejan Mamula Jan Kehr Justyna Zareba-Paslawska Henrik Biverstål Karima Chergui Xiaoqun Zhang Per E. Andren Per Svenningsson Prosaposin maintains lipid homeostasis in dopamine neurons and counteracts experimental parkinsonism in rodents Nature Communications |
| title | Prosaposin maintains lipid homeostasis in dopamine neurons and counteracts experimental parkinsonism in rodents |
| title_full | Prosaposin maintains lipid homeostasis in dopamine neurons and counteracts experimental parkinsonism in rodents |
| title_fullStr | Prosaposin maintains lipid homeostasis in dopamine neurons and counteracts experimental parkinsonism in rodents |
| title_full_unstemmed | Prosaposin maintains lipid homeostasis in dopamine neurons and counteracts experimental parkinsonism in rodents |
| title_short | Prosaposin maintains lipid homeostasis in dopamine neurons and counteracts experimental parkinsonism in rodents |
| title_sort | prosaposin maintains lipid homeostasis in dopamine neurons and counteracts experimental parkinsonism in rodents |
| url | https://doi.org/10.1038/s41467-023-41539-5 |
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