2. Academic Validation
  3. Genetically modified E. Coli secreting melanin (E.melanin) activates the astrocytic PSAP-GPR37L1 pathway and mitigates the pathogenesis of Parkinson's disease

Genetically modified E. Coli secreting melanin (E.melanin) activates the astrocytic PSAP-GPR37L1 pathway and mitigates the pathogenesis of Parkinson's disease

  • J Nanobiotechnology. 2024 Nov 10;22(1):690. doi: 10.1186/s12951-024-02955-x.
Weixian Kong # 1,  Yu Liu # 1,  Pu Ai # 1,  Yong Bi # 2,  Chaoguang Wei 3,  Xiaoyang Guo 1 4,  Zhenyu Cai 5 6,  Ge Gao 4,  Peng Hu 3,  Jialin Zheng 4,  Jianhui Liu 7,  Minfeng Huo 8,  Yuting Guan 9,  Qihui Wu 10
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Neurology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, 1500 Zhouyuan Road, Pudong New Area, Shanghai, 201318, China.
  • 3 Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai, 201306, China.
  • 4 Center for Translational Neurodegeneration and Regenerative Therapy, Tongji Hospital, Shanghai Frontiers Science Center of Nanocatalytic Medicine, The Institute for Biomedical Engineering & Nano Science, School of Medicine, Tongji University School of Medicine, Tongji University, Shanghai, 200092, China.
  • 5 Cancer Center, Tenth Peoples Hospital of Tongji University, Shanghai, 200070, China.
  • 6 College of Pharmacy, Ningxia Medical University, Ningxia Hui Autonomous Region, Yinchuan, 750004, China.
  • 7 Department of Anaesthesiology, School of Medicine, Tongji Hospital, Tongji University, Shanghai, China. jianhuiliu_1246@163.com.
  • 8 Shanghai Frontiers Science Center of Nanocatalytic Medicine, School of Medicine, Shanghai Tenth People's Hospital, Tongji University, Shanghai, 200072, China. mfhuo@tongji.edu.cn.
  • 9 Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, 200241, China. ytguan@bio.ecnu.edu.cn.
  • 10 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. qihuiwu@tongji.edu.cn.
  • # Contributed equally.
PMID: 39523310 DOI: 10.1186/s12951-024-02955-x
Abstract

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.

Keywords

Astrocyte; Dopamine neuron; Melanin; PSAP-GPR37L1 pathway; Parkinson’s disease.

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