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Exosomes from patients with Parkinson’s disease are pathological in mice

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Abstract

Cell-to-cell transport of risk molecules is a highly anticipated pathogenic mechanism in the initiation and progression of various neurodegenerative diseases. Extracellular exosome-mediated neuron to neuron transport of α-synuclein (α-syn) is increasingly recognized as a potential etiologic mechanism in Parkinson’s disease (PD). Exosomal inflammation has also been increasingly implicated in PD pathogenesis and could trigger, facilitate, or aggravate disease development. However, these mechanisms have not been verified systematically, especially in vivo. Since serum contains abundant exosomes, the correlation between serum exosomes and PD pathogenesis remains unknown. Here, we show that exosomes from PD patient serum contain more α-syn and inflammatory factors such as IL-1β and TNF-α than neurological normal controls, eventually cause α-syn, ubiquitin, and P62 aggregation in recipient cells. More importantly, the intravenous or intrastriatal treatment of mice with exosomes from PD patient serum could evoke protein aggregation, trigger dopamine neuron degeneration, induce microglial activation, and cause apomorphine-coaxed rotation and movement defects. All these findings imply the exosome pathway as a new pathogenesis mechanism for PD, and therefore may present new targets for therapeutics.

Key messages

  • We have presented the evidence for a relationship between PD (Parkinson’s disease) patients’ serum exosomes and pathogenesis.

  • PD patients’ serum-derived exosomes could induce α-syn, ubiquitin and P62 aggregation in recipient cells.

  • Intravenous or intrastriatal treatments of mice with PD exosomes were able to recapitulate the molecular, cellular and behavioral phenotypes of PD.

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Funding

This work was supported by grants 81671260 (to TW) and 81471305 (to TW), 81873782 (to NX) and 81301082 (to JSH) from the National Natural Science Foundation of China, grants 2017YFC1310200 (to TW), 2016YFC1306000 (to TW), 2016YFC1306600 (to NX), and 2018YFC1314700 (to NX) from the National Key R&D Program of China, Grant 2016CFB624 from Natural Science Foundation of Hubei Province (to NX), Grant 2017050304010278 from The Youth Science and Technology Morning Light Program of Wuhan City (to NX), 2018 Hubei Medical Research Project WJ2019F030 (to NX), 2018 Wuhan Medical Research Project S201802140011 (to NX), 2018 Wuhan Young and Middle-aged Medical Talents Program (to NX) and 2017 Hubei Provincial Party Committee Organization Department the Second Batch of Hubei Youth Elite Development Plan (to NX) and US NIH DA021409 (ZL).

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Author notes

  1. Chao Han, Nian Xiong and Xingfang Guo contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Road, Wuhan, 430022, Hubei, China

    Chao Han, Nian Xiong, Xingfang Guo, Jinsha Huang, Kai Ma, Ling Liu, Yun Xia, Yan Shen, Jie Li, Haiyang Jiang, Luxi Wang, Shiyi Guo, Xiaoyun Xu, Guoxin Zhang, Xuebing Cao & Tao Wang

  2. Department of Neurology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, Anhui, China

    Chao Han

  3. Department of Neurology, People’s Hospital of Dongxihu District, Wuhan, 430040, Hubei, China

    Nian Xiong

  4. Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Centre for Genome Research, Huazhong University of Science and Technology, Wuhan, 430074, Hubei, China

    Jingyu Liu

  5. Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China

    Zhentao Zhang

  6. Department of Psychiatry, Harvard Medical School; Division of Basic Neuroscience, and Mailman Neuroscience Research Center, McLean Hospital, Belmont, MA, 02478, USA

    Zhicheng Lin

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  1. Chao Han
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Contributions

Author T. W designed the study. Author C. H, N. X and X.F.G participated in performing the research. Author J.S.H, J.Y.L, X.B.C, and Z.C.L revised this manuscript. Author K. M and L. L raised the animals. Author Y. X, Y. S, J. L, and H.Y.J collected the blood sample. L.X.W and S.Y.G isolated the exosomes. X.Y.X and Z.T.Z managed the literature searches and analyses. Author G.X. Z undertook the statistical analysis. All authors participated in writing and reviewing the manuscript.

Corresponding author

Correspondence to Tao Wang.

Ethics declarations

All procedures performed in studies involving human participants were approved by the ethics committee of Tongji Medical College, Huazhong University of Science and Technology. All animal experiments were ethically approved by the Institutional Animal Ethical Committee of Tongji Medical College, Huazhong University of Science and Technology. Informed consent was obtained from all individual participants in the study.

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The authors declare that they have no conflict of interest.

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Zhicheng Lin Joint last author

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Han, C., Xiong, N., Guo, X. et al. Exosomes from patients with Parkinson’s disease are pathological in mice. J Mol Med 97, 1329–1344 (2019). https://doi.org/10.1007/s00109-019-01810-z

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