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

IF 6.9 1区生物学 Q1 CELL BIOLOGY Cell reports Pub Date : 2025-02-25 Epub Date: 2025-02-04 DOI:10.1016/j.celrep.2025.115266

Qiang Ma, Jin-Lan Tian, Yao Lou, Ran Guo, Xiao-Ru Ma, Jian-Bin Wu, Jing Yang, Bing-Jie Tang, Shun Li, Mengsheng Qiu, Shumin Duan, Jing-Wei Zhao, Jing Zhang, Zhen-Zhong Xu

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Abstract

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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少突胶质细胞通过prosaposin-GPR37-IL-6轴驱动帕金森病的神经炎症和神经变性。

帕金森病（PD）是一种常见的神经退行性疾病，其发病机制尚不明确，治疗难度较大。最近的研究发现少突胶质细胞与PD的进展之间存在显著的联系，但少突胶质细胞如何调节PD的发病机制仍不清楚。本研究表明，帕金森小鼠黑质少突胶质细胞中g蛋白偶联受体37 （GPR37）表达上调，丙皂素（PSAP）分泌增加。释放的PSAP可通过gpr37依赖途径诱导少突胶质细胞白细胞介素(IL)-6上调和分泌，导致神经炎症增强、多巴胺神经元变性和行为缺陷。少突胶质细胞GPR37缺乏可预防多种PD模型的神经退行性变。最后，在PD患者中观察PSAP-GPR37-IL-6轴的特征。因此，我们的研究结果表明，多巴胺能神经元通过分泌PSAP与少突胶质细胞相互作用，我们的研究结果确定PSAP- gpr37 - il -6轴是PD发病机制的驱动因素，也是可能缓解PD患者进展的潜在治疗靶点。

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来源期刊

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

期刊介绍： Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.