G6PD deficiency triggers dopamine loss and the initiation of Parkinson’s disease pathogenesis
Summary: Loss of dopaminergic neurons in Parkinson’s disease (PD) is preceded by loss of synaptic dopamine (DA) and accumulation of proteinaceous aggregates. Linking these deficits is critical to restoring DA signaling in PD. Using murine and human pluripotent stem cell (hPSC) models of PD coupled w...
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| Language: | English |
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Elsevier
2025-01-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124724015298 |
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| author | Morgan G. Stykel Shehani V. Siripala Eric Soubeyrand Carla L. Coackley Ping Lu Suelen Camargo Sharanya Thevasenan Gerardo Balderas Figueroa Raphaella W.L. So Erica Stuart Rachi Panchal Elissavet-Kalliopi Akrioti Jeffery T. Joseph Omid Haji-Ghassemi Era Taoufik Tariq A. Akhtar Joel C. Watts Scott D. Ryan |
| author_facet | Morgan G. Stykel Shehani V. Siripala Eric Soubeyrand Carla L. Coackley Ping Lu Suelen Camargo Sharanya Thevasenan Gerardo Balderas Figueroa Raphaella W.L. So Erica Stuart Rachi Panchal Elissavet-Kalliopi Akrioti Jeffery T. Joseph Omid Haji-Ghassemi Era Taoufik Tariq A. Akhtar Joel C. Watts Scott D. Ryan |
| author_sort | Morgan G. Stykel |
| collection | DOAJ |
| description | Summary: Loss of dopaminergic neurons in Parkinson’s disease (PD) is preceded by loss of synaptic dopamine (DA) and accumulation of proteinaceous aggregates. Linking these deficits is critical to restoring DA signaling in PD. Using murine and human pluripotent stem cell (hPSC) models of PD coupled with human postmortem tissue, we show that accumulation of α-syn micro-aggregates impairs metabolic flux through the pentose phosphate pathway (PPP). This leads to decreased nicotinamide adenine dinucleotide phosphate (NADP/H) and glutathione (GSH) levels, resulting in DA oxidation and decreased total DA levels. We find that α-syn anchors the PPP enzyme G6PD to synaptic vesicles via the α-syn C terminus and that this interaction is lost in PD. Furthermore, G6PD clinical mutations are associated with PD diagnosis, and G6PD deletion phenocopies PD pathology. Finally, we show that restoring NADPH or GSH levels through genetic and pharmacological intervention blocks DA oxidation and rescues steady-state DA levels, identifying G6PD as a pharmacological target against PD. |
| format | Article |
| id | doaj-art-b44e06693c944797a80bcacca38a4e46 |
| institution | Kabale University |
| issn | 2211-1247 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj-art-b44e06693c944797a80bcacca38a4e462025-01-08T04:52:25ZengElsevierCell Reports2211-12472025-01-01441115178G6PD deficiency triggers dopamine loss and the initiation of Parkinson’s disease pathogenesisMorgan G. Stykel0Shehani V. Siripala1Eric Soubeyrand2Carla L. Coackley3Ping Lu4Suelen Camargo5Sharanya Thevasenan6Gerardo Balderas Figueroa7Raphaella W.L. So8Erica Stuart9Rachi Panchal10Elissavet-Kalliopi Akrioti11Jeffery T. Joseph12Omid Haji-Ghassemi13Era Taoufik14Tariq A. Akhtar15Joel C. Watts16Scott D. Ryan17Department of Molecular and Cellular Biology, The University of Guelph, Guelph ON, CanadaDepartment of Molecular and Cellular Biology, The University of Guelph, Guelph ON, Canada; Department of Clinical Neuroscience, University of Calgary, Calgary, AB, CanadaDepartment of Molecular and Cellular Biology, The University of Guelph, Guelph ON, CanadaDepartment of Molecular and Cellular Biology, The University of Guelph, Guelph ON, CanadaDepartment of Clinical Neuroscience, University of Calgary, Calgary, AB, CanadaDepartment of Clinical Neuroscience, University of Calgary, Calgary, AB, CanadaDepartment of Clinical Neuroscience, University of Calgary, Calgary, AB, CanadaDepartment of Clinical Neuroscience, University of Calgary, Calgary, AB, CanadaTanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada; Department of Biochemistry, University of Toronto, Toronto, ON, CanadaTanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada; Department of Biochemistry, University of Toronto, Toronto, ON, CanadaBiological Sciences, Hellenic Pasteur Institute, Athens, GreeceLaboratory of Cellular and Molecular Neurobiology-Stem Cells, Hellenic Pasteur Institute, Athens, GreeceDepartment of Pathology and Laboratory Medicine, University of Calgary, Calgary, AB, CanadaDepartment of Biological Sciences, University of Calgary, Calgary, AB, CanadaLaboratory of Cellular and Molecular Neurobiology-Stem Cells, Hellenic Pasteur Institute, Athens, GreeceDepartment of Molecular and Cellular Biology, The University of Guelph, Guelph ON, CanadaTanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada; Department of Biochemistry, University of Toronto, Toronto, ON, CanadaDepartment of Molecular and Cellular Biology, The University of Guelph, Guelph ON, Canada; Department of Clinical Neuroscience, University of Calgary, Calgary, AB, Canada; Corresponding authorSummary: Loss of dopaminergic neurons in Parkinson’s disease (PD) is preceded by loss of synaptic dopamine (DA) and accumulation of proteinaceous aggregates. Linking these deficits is critical to restoring DA signaling in PD. Using murine and human pluripotent stem cell (hPSC) models of PD coupled with human postmortem tissue, we show that accumulation of α-syn micro-aggregates impairs metabolic flux through the pentose phosphate pathway (PPP). This leads to decreased nicotinamide adenine dinucleotide phosphate (NADP/H) and glutathione (GSH) levels, resulting in DA oxidation and decreased total DA levels. We find that α-syn anchors the PPP enzyme G6PD to synaptic vesicles via the α-syn C terminus and that this interaction is lost in PD. Furthermore, G6PD clinical mutations are associated with PD diagnosis, and G6PD deletion phenocopies PD pathology. Finally, we show that restoring NADPH or GSH levels through genetic and pharmacological intervention blocks DA oxidation and rescues steady-state DA levels, identifying G6PD as a pharmacological target against PD.http://www.sciencedirect.com/science/article/pii/S2211124724015298CP: Neuroscience |
| spellingShingle | Morgan G. Stykel Shehani V. Siripala Eric Soubeyrand Carla L. Coackley Ping Lu Suelen Camargo Sharanya Thevasenan Gerardo Balderas Figueroa Raphaella W.L. So Erica Stuart Rachi Panchal Elissavet-Kalliopi Akrioti Jeffery T. Joseph Omid Haji-Ghassemi Era Taoufik Tariq A. Akhtar Joel C. Watts Scott D. Ryan G6PD deficiency triggers dopamine loss and the initiation of Parkinson’s disease pathogenesis Cell Reports CP: Neuroscience |
| title | G6PD deficiency triggers dopamine loss and the initiation of Parkinson’s disease pathogenesis |
| title_full | G6PD deficiency triggers dopamine loss and the initiation of Parkinson’s disease pathogenesis |
| title_fullStr | G6PD deficiency triggers dopamine loss and the initiation of Parkinson’s disease pathogenesis |
| title_full_unstemmed | G6PD deficiency triggers dopamine loss and the initiation of Parkinson’s disease pathogenesis |
| title_short | G6PD deficiency triggers dopamine loss and the initiation of Parkinson’s disease pathogenesis |
| title_sort | g6pd deficiency triggers dopamine loss and the initiation of parkinson s disease pathogenesis |
| topic | CP: Neuroscience |
| url | http://www.sciencedirect.com/science/article/pii/S2211124724015298 |
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