Oligodendrocytes drive neuroinflammation and neurodegeneration in Parkinson’s disease via the prosaposin-GPR37-IL-6 axis
Summary: Parkinson’s disease (PD) is a common neurodegenerative disease and is difficult to treat due to its elusive mechanisms. Recent studies have identified a striking association between oligodendrocytes and PD progression, yet how oligodendrocytes regulate the pathogenesis of PD is still unknow...
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| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-02-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124725000373 |
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| Summary: | Summary: Parkinson’s disease (PD) is a common neurodegenerative disease and is difficult to treat due to its elusive mechanisms. Recent studies have identified a striking association between oligodendrocytes and PD progression, yet how oligodendrocytes regulate the pathogenesis of PD is still unknown. Here, we show that G-protein-coupled receptor 37 (GPR37) is upregulated in oligodendrocytes of the substantia nigra and that prosaposin (PSAP) secretion is increased in parkinsonian mice. The released PSAP can induce interleukin (IL)-6 upregulation and secretion from oligodendrocytes via a GPR37-dependent pathway, resulting in enhanced neuroinflammation, dopamine neuron degeneration, and behavioral deficits. GPR37 deficiency in oligodendrocytes prevents neurodegeneration in multiple PD models. Finally, the hallmarks of the PSAP-GPR37-IL-6 axis are observed in patients with PD. Thus, our results reveal that dopaminergic neurons interact with oligodendrocytes via secreted PSAP, and our findings identify the PSAP-GPR37-IL-6 axis as a driver of PD pathogenesis and a potential therapeutic target that might alleviate PD progression in patients. |
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| ISSN: | 2211-1247 |