Oligodendrocytes drive neuroinflammation and neurodegeneration in Parkinson's disease via the prosaposin-GPR37-IL-6 axis.

1. Cell Rep. 2025 Feb 25;44(2):115266. doi: 10.1016/j.celrep.2025.115266. Epub 2025 Feb 4. Oligodendrocytes drive neuroinflammation and neurodegeneration in Parkinson's disease via the prosaposin-GPR37-IL-6 axis. Ma Q(1), Tian JL(2), Lou Y(3), Guo R(4), Ma XR(5), Wu JB(5), Yang J(6), Tang BJ(2), Li S(3), Qiu M(7), Duan S(2), Zhao JW(5), Zhang J(8), Xu ZZ(9). Author information: (1)Department of Anesthesiology of First Affiliated Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China; Center for Rehabilitation Medicine, Department of Anesthesiology and Department of Pain Management, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou 310014, China; Liangzhu Laboratory, MOE Frontier Science Center for Brain Science and Brain-machine Integration, State Key Laboratory of Brain-machine Intelligence, Zhejiang University, Hangzhou 311121, China. Electronic address: 0618339@zju.edu.cn. (2)Department of Anesthesiology of First Affiliated Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China; Liangzhu Laboratory, MOE Frontier Science Center for Brain Science and Brain-machine Integration, State Key Laboratory of Brain-machine Intelligence, Zhejiang University, Hangzhou 311121, China; Nanhu Brain-Computer Interface Institute, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University, Hangzhou 311100, China. (3)Center for Rehabilitation Medicine, Department of Anesthesiology and Department of Pain Management, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou 310014, China. (4)Center for Rehabilitation Medicine, Department of Anesthesiology and Department of Pain Management, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou 310014, China. Electronic address: guoranxs@126.com. (5)Department of Pathology of Sir Run Run Shaw Hospital and Department of Human Anatomy, Histology and Embryology, System Medicine Research Center, Zhejiang University School of Medicine, Hangzhou 310058, China. (6)Department of Anesthesiology of First Affiliated Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China; Center for Rehabilitation Medicine, Department of Anesthesiology and Department of Pain Management, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou 310014, China. (7)Zhejiang Key Laboratory of Organ Development and Regeneration, Institute of Life Sciences, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou 311121, China. (8)Department of Anesthesiology of First Affiliated Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China; Liangzhu Laboratory, MOE Frontier Science Center for Brain Science and Brain-machine Integration, State Key Laboratory of Brain-machine Intelligence, Zhejiang University, Hangzhou 311121, China; Department of Pathology of First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310002, China; National Health and Disease Human Brain Tissue Resource Center, Zhejiang University, Hangzhou 310002, China. (9)Department of Anesthesiology of First Affiliated Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China; Liangzhu Laboratory, MOE Frontier Science Center for Brain Science and Brain-machine Integration, State Key Laboratory of Brain-machine Intelligence, Zhejiang University, Hangzhou 311121, China; Nanhu Brain-Computer Interface Institute, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University, Hangzhou 311100, China. Electronic address: xuzz@zju.edu.cn. 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