Shanghai Research Institute for Intelligent Autonomous Systems, Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Clinical Research Center for Anesthesiology and Perioperative Medicine, Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People's Hospital Affiliated to Tongji University School of Medicine, State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China.
Department of Neurology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, 1500 Zhouyuan Road, Pudong New Area, Shanghai, 201318, China.
J Nanobiotechnology. 2024 Nov 10;22(1):690. doi: 10.1186/s12951-024-02955-x.
The characteristic neuropathology of Parkinson's disease (PD) involves the abnormal accumulation of phosphorylated α-synuclein (αSyn), as well as a significant decrease in neuromelanin (NM) levels within dopamine neurons (DaNs). Unlike αSyn aggregates, the relationship between NM levels and PD pathogenesis is not well understood. In this study, we engineered an E. coli MG1655 strain to produce exosomes containing melanin (E.melanin), and investigated its potential neuroprotective effects on DaNs in the context of PD. By employing a combination of cell cultures, biochemical studies, single nuclear RNA sequencing (snRNA seq), and various in vivo validations, we found that administration of E.melanin effectively alleviated DaNs loss and improved motor behavior impairments observed in both pharmacological and transgenic PD mouse models. Mechanistically, snRNA seq data suggested that E.melanin activated the PSAP-GPR37L1 signaling pathway specifically within astrocytes, leading to a reduction in astrocytic engulfment of synapses. Notably, activation of the GPR37L1 receptor using Tx14(A) peptide successfully rescued motor defects as well as protected against DaNs degeneration in mice with PD. Overall, our findings provide novel insights into understanding the molecular mechanisms underlying melanin's protective effects on DaNs in PD while offering potential strategies for manipulating and treating its pathophysiological progression.
帕金森病（PD）的特征性神经病理学涉及磷酸化α-突触核蛋白（αSyn）的异常积累，以及多巴胺神经元（DaNs）内神经黑色素（NM）水平的显著降低。与αSyn 聚集物不同，NM 水平与 PD 发病机制之间的关系尚不清楚。在这项研究中，我们设计了一种大肠杆菌 MG1655 菌株来生产含有黑色素的外泌体（E.melanin），并研究了其在 PD 背景下对 DaNs 的潜在神经保护作用。通过结合细胞培养、生化研究、单个核 RNA 测序（snRNA seq）和各种体内验证，我们发现 E.melanin 的给药有效缓解了药物和转基因 PD 小鼠模型中观察到的 DaNs 损失，并改善了运动行为障碍。从机制上讲，snRNA seq 数据表明，E.melanin 特异性地在星形胶质细胞中激活了 PSAP-GPR37L1 信号通路，导致星形胶质细胞对突触的吞噬作用减少。值得注意的是，使用 Tx14(A) 肽激活 GPR37L1 受体成功挽救了运动缺陷，并保护了 PD 小鼠的 DaNs 退化。总体而言，我们的研究结果为理解黑色素对 PD 中 DaNs 的保护作用的分子机制提供了新的见解，并为操纵和治疗其病理生理进展提供了潜在的策略。
