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

  • 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
  • Jingyu Liu
  • Xuebing Cao
  • Zhentao Zhang
  • Zhicheng Lin
  • Tao WangEmail author
Original Article


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.


Parkinson’s disease Exosomes α-synuclein Pathogenesis 


Author 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.

Funding information

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).

Compliance with ethical standards

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.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

109_2019_1810_Fig9_ESM.png (146 kb)

(PNG 146 kb)

109_2019_1810_MOESM1_ESM.tif (13.7 mb)
High Resolution Image (TIF 14020 kb)
109_2019_1810_Fig10_ESM.png (619 kb)

(PNG 619 kb)

109_2019_1810_MOESM2_ESM.tif (826 kb)
High Resolution Image (TIF 826 kb)
109_2019_1810_Fig11_ESM.png (173 kb)

(PNG 173 kb)

109_2019_1810_MOESM3_ESM.tif (256 kb)
High Resolution Image (TIF 256 kb)
109_2019_1810_MOESM4_ESM.png (30.3 mb)
ESM 4 (PNG 31059 kb)
109_2019_1810_Fig12_ESM.png (111 kb)

(PNG 111 kb)

109_2019_1810_MOESM5_ESM.tif (177 kb)
High Resolution Image (TIF 177 kb)
109_2019_1810_Fig13_ESM.png (489 kb)

(PNG 488 kb)

109_2019_1810_MOESM6_ESM.tif (646 kb)
High Resolution Image (TIF 646 kb)
109_2019_1810_MOESM11_ESM.docx (33 kb)
ESM 8 (DOCX 33 kb)
109_2019_1810_MOESM8_ESM.mp4 (3.5 mb)
ESM 10 (MP4 3537 kb)


  1. 1.
    Jucker M, Walker LC (2013) Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature 501:45–51CrossRefGoogle Scholar
  2. 2.
    Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E (2003) Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging 24:197–211CrossRefGoogle Scholar
  3. 3.
    Li JY, Englund E, Holton JL, Soulet D, Hagell P, Lees AJ, Lashley T, Quinn NP, Rehncrona S, Bjorklund A et al (2008) Lewy bodies in grafted neurons in subjects with Parkinson's disease suggest host-to-graft disease propagation. Nat Med 14:501–503CrossRefGoogle Scholar
  4. 4.
    McCann H, Cartwright H, Halliday GM (2016) Neuropathology of alpha-synuclein propagation and Braak hypothesis. Mov Disord 31:152–160CrossRefGoogle Scholar
  5. 5.
    Guo JL, Lee VM (2014) Cell-to-cell transmission of pathogenic proteins in neurodegenerative diseases. Nat Med 20:130–138CrossRefGoogle Scholar
  6. 6.
    Han C, Sun X, Liu L, Jiang H, Shen Y, Xu X, Li J, Zhang G, Huang J, Lin Z, Xiong N, Wang T (2016) Exosomes and their therapeutic potentials of stem cells. Stem Cells Int 2016:7653489Google Scholar
  7. 7.
    Thery C, Zitvogel L, Amigorena S (2002) Exosomes: composition, biogenesis and function. Nat Rev Immunol 2:569–579CrossRefGoogle Scholar
  8. 8.
    Tkach M, Thery C (2016) Communication by extracellular vesicles: where we are and where we need to go. Cell 164:1226–1232CrossRefGoogle Scholar
  9. 9.
    Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO (2007) Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 9:654–659CrossRefGoogle Scholar
  10. 10.
    Gupta A, Pulliam L (2014) Exosomes as mediators of neuroinflammation. J Neuroinflammation 11:68CrossRefGoogle Scholar
  11. 11.
    Stuendl A, Kunadt M, Kruse N, Bartels C, Moebius W, Danzer KM, Mollenhauer B, Schneider A (2016) Induction of alpha-synuclein aggregate formation by CSF exosomes from patients with Parkinson's disease and dementia with Lewy bodies. Brain 139:481–494CrossRefGoogle Scholar
  12. 12.
    Peelaerts W, Bousset L, Van der Perren A, Moskalyuk A, Pulizzi R, Giugliano M, Van den Haute C, Melki R, Baekelandt V (2015) Alpha-synuclein strains cause distinct synucleinopathies after local and systemic administration. Nature 522:340–344CrossRefGoogle Scholar
  13. 13.
    Postuma RB, Berg D, Stern M, Poewe W, Olanow CW, Oertel W, Obeso J, Marek K, Litvan I, Lang AE, Halliday G, Goetz CG, Gasser T, Dubois B, Chan P, Bloem BR, Adler CH, Deuschl G (2015) MDS clinical diagnostic criteria for Parkinson's disease. Mov Disord 30:1591–1601CrossRefGoogle Scholar
  14. 14.
    Trajkovic K, Hsu C, Chiantia S, Rajendran L, Wenzel D, Wieland F, Schwille P, Brugger B, Simons M (2008) Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science 319:1244–1247CrossRefGoogle Scholar
  15. 15.
    Li P, Kaslan M, Lee SH, Yao J, Gao Z (2017) Progress in exosome isolation techniques. Theranostics 7:789–804CrossRefGoogle Scholar
  16. 16.
    Oyarce AM, Fleming PJ (1991) Multiple forms of human dopamine beta-hydroxylase in SH-SY5Y neuroblastoma cells. Arch Biochem Biophys 290:503–510CrossRefGoogle Scholar
  17. 17.
    Lee BR, Kamitani T (2011) Improved immunodetection of endogenous alpha-synuclein. Plos One 6:e23939CrossRefGoogle Scholar
  18. 18.
    Liu W, Li Y, Jalewa J, Saunders-Wood T, Li L, Holscher C (2015) Neuroprotective effects of an oxyntomodulin analogue in the MPTP mouse model of Parkinson's disease. Eur J Pharmacol 765:284–290CrossRefGoogle Scholar
  19. 19.
    Nie S, Xu Y, Chen G, Ma K, Han C, Guo Z, Zhang Z, Ye K, Cao X (2015) Small molecule TrkB agonist deoxygedunin protects nigrostriatal dopaminergic neurons from 6-OHDA and MPTP induced neurotoxicity in rodents. Neuropharmacology 99:448–458CrossRefGoogle Scholar
  20. 20.
    Danzer KM, Kranich LR, Ruf WP, Cagsal-Getkin O, Winslow AR, Zhu LY, Vanderburg CR, McLean PJ (2012) Exosomal cell-to-cell transmission of alpha synuclein oligomers. Mol Neurodegener 7:42CrossRefGoogle Scholar
  21. 21.
    Shi M, Liu C, Cook TJ, Bullock KM, Zhao Y, Ginghina C, Li Y, Aro P, Dator R, He C, Hipp MJ, Zabetian CP, Peskind ER, Hu SC, Quinn JF, Galasko DR, Banks WA, Zhang J (2014) Plasma exosomal alpha-synuclein is likely CNS-derived and increased in Parkinson's disease. Acta Neuropathol 128:639–650CrossRefGoogle Scholar
  22. 22.
    Winner B, Jappelli R, Maji SK, Desplats PA, Boyer L, Aigner S, Hetzer C, Loher T, Vilar M, Campioni S, Tzitzilonis C, Soragni A, Jessberger S, Mira H, Consiglio A, Pham E, Masliah E, Gage FH, Riek R (2011) In vivo demonstration that alpha-synuclein oligomers are toxic. Proc Natl Acad Sci U S A 108:4194–4199CrossRefGoogle Scholar
  23. 23.
    Luk KC, Kehm V, Carroll J, Zhang B, O'Brien P, Trojanowski JQ, Lee VMY (2012) Pathological alpha-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science 338:949–953CrossRefGoogle Scholar
  24. 24.
    Masuda-Suzukake M, Nonaka T, Hosokawa M, Oikawa T, Arai T, Akiyama H, Mann DM, Hasegawa M (2013) Prion-like spreading of pathological alpha-synuclein in brain. Brain 136:1128–1138CrossRefGoogle Scholar
  25. 25.
    Goedert M, Spillantini MG, Del Tredici K, Braak H (2013) 100 years of Lewy pathology. Nat Rev Neurol 9:13–24CrossRefGoogle Scholar
  26. 26.
    Recasens A, Dehay B, Bove J, Carballo-Carbajal I, Dovero S, Perez-Villalba A, Fernagut PO, Blesa J, Parent A, Perier C et al (2014) Lewy body extracts from Parkinson disease brains trigger alpha-synuclein pathology and neurodegeneration in mice and monkeys. Ann Neurol 75:351–362CrossRefGoogle Scholar
  27. 27.
    Minakaki G, Menges S, Kittel A, Emmanouilidou E, Schaeffner I, Barkovits K, Bergmann A, Rockenstein E, Adame A, Marxreiter F, Mollenhauer B, Galasko D, Buzás EI, Schlötzer-Schrehardt U, Marcus K, Xiang W, Lie DC, Vekrellis K, Masliah E, Winkler J, Klucken J (2018) Autophagy inhibition promotes SNCA/alpha-synuclein release and transfer via extracellular vesicles with a hybrid autophagosome-exosome-like phenotype. Autophagy 14:98–119CrossRefGoogle Scholar
  28. 28.
    Kim S, Yun SP, Lee S, Umanah GE, Bandaru VVR, Yin XL, Rhee P, Karuppagounder SS, Kwon SH, Lee H, Mao X, Kim D, Pandey A, Lee G, Dawson VL, Dawson TM, Ko HS (2018) GBA1 deficiency negatively affects physiological alpha-synuclein tetramers and related multimers. Proc Natl Acad Sci U S A 115:798–803CrossRefGoogle Scholar
  29. 29.
    Tentillier N, Etzerodt A, Olesen MN, Rizalar FS, Jacobsen J, Bender D, Moestrup SK, Romero-Ramos M (2016) Anti-inflammatory modulation of microglia via CD163-targeted glucocorticoids protects dopaminergic neurons in the 6-OHDA Parkinson's disease model. J Neurosci 36:9375–9390CrossRefGoogle Scholar
  30. 30.
    Streit WJ, Mrak RE, Griffin WS (2004) Microglia and neuroinflammation: a pathological perspective. J Neuroinflammation 1:14CrossRefGoogle Scholar
  31. 31.
    Bauernfeind FG, Horvath G, Stutz A, Alnemri ES, MacDonald K, Speert D, Fernandes-Alnemri T, Wu J, Monks BG, Fitzgerald KA, Hornung V, Latz E (2009) Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J Immunol 183:787–791CrossRefGoogle Scholar
  32. 32.
    Edgren G, Hjalgrim H, Rostgaard K, Lambert P, Wikman A, Norda R, Titlestad KE, Erikstrup C, Ullum H, Melbye M, Busch MP, Nyrén O (2016) Transmission of neurodegenerative disorders through blood transfusion a cohort study. Ann Intern Med 165:316–324CrossRefGoogle Scholar
  33. 33.
    Bu XL, Xiang Y, Jin WS, Wang J, Shen LL, Huang ZL, Zhang K, Liu YH, Zeng F, Liu JH, Sun HL, Zhuang ZQ, Chen SH, Yao XQ, Giunta B, Shan YC, Tan J, Chen XW, Dong ZF, Zhou HD, Zhou XF, Song W, Wang YJ (2017) Blood-derived amyloid-beta protein induces Alzheimer's disease pathologies. Mol Psychiatry 23:1948–1956CrossRefGoogle Scholar
  34. 34.
    Middeldorp J, Lehallier B, Villeda SA, Miedema SS, Evans E, Czirr E, Zhang H, Luo J, Stan T, Mosher KI et al (2016) Preclinical assessment of young blood plasma for Alzheimer disease. JAMA Neurol 73:1325–1333CrossRefGoogle Scholar
  35. 35.
    Villeda SA, Plambeck KE, Middeldorp J, Castellano JM, Mosher KI, Luo J, Smith LK, Bieri G, Lin K, Berdnik D, Wabl R, Udeochu J, Wheatley EG, Zou B, Simmons DA, Xie XS, Longo FM, Wyss-Coray T (2014) Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nat Med 20:659–663CrossRefGoogle Scholar
  36. 36.
    Emmanouilidou E, Melachroinou K, Roumeliotis T, Garbis SD, Ntzouni M, Margaritis LH, Stefanis L, Vekrellis K (2010) Cell-produced alpha-synuclein is secreted in a calcium-dependent manner by exosomes and impacts neuronal survival. J Neurosci 30:6838–6851CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Chao Han
    • 1
    • 2
  • Nian Xiong
    • 1
    • 3
  • Xingfang Guo
    • 1
  • Jinsha Huang
    • 1
  • Kai Ma
    • 1
  • Ling Liu
    • 1
  • Yun Xia
    • 1
  • Yan Shen
    • 1
  • Jie Li
    • 1
  • Haiyang Jiang
    • 1
  • Luxi Wang
    • 1
  • Shiyi Guo
    • 1
  • Xiaoyun Xu
    • 1
  • Guoxin Zhang
    • 1
  • Jingyu Liu
    • 4
  • Xuebing Cao
    • 1
  • Zhentao Zhang
    • 5
  • Zhicheng Lin
    • 6
  • Tao Wang
    • 1
    Email author
  1. 1.Department of Neurology, Union Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
  2. 2.Department of Neurology, the First Affiliated Hospital of USTC, Division of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiChina
  3. 3.Department of NeurologyPeople’s Hospital of Dongxihu DistrictWuhanChina
  4. 4.Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Centre for Genome ResearchHuazhong University of Science and TechnologyWuhanChina
  5. 5.Department of NeurologyRenmin Hospital of Wuhan UniversityWuhanChina
  6. 6.Department of Psychiatry, Harvard Medical School; Division of Basic Neuroscience, and Mailman Neuroscience Research CenterMcLean HospitalBelmontUSA

Personalised recommendations