Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Addition of α-synuclein aggregates to the intestinal environment recapitulates Parkinsonian symptoms in model systems

Acta Pharmacologica Sinica volume 45, pages 36–51 (2024)Cite this article

Abstract

The gut-brain axis plays a vital role in Parkinson’s disease (PD). The mechanisms of gut-brain transmission mainly focus on α-synuclein deposition, intestinal inflammation and microbiota function. A few studies have shown the trigger of PD pathology in the gut. α-Synuclein is highly conserved in food products, which was able to form β-folded aggregates and to infect the intestinal mucosa. In this study we investigated whether α-synuclein-preformed fibril (PFF) exposure could modulate the intestinal environment and induce rodent models replicating PD pathology. We first showed that PFF could be internalized into co-cultured Caco-2/HT29/Raji b cells in vitro. Furthermore, we demonstrated that PFF perfusion caused the intestinal inflammation and activation of enteric glial cells in an ex vivo intestinal organ culture and in an in vivo intestinal mouse coloclysis model. Moreover, we found that PFF exposure through regular coloclysis induced PD pathology in wild-type (WT) and A53T α-synuclein transgenic mice with various phenotypes. Particularly in A53T mice, PFF induced significant behavioral disorders, intestinal inflammation, α-synuclein deposition, microbiota dysbiosis, glial activation as well as degeneration of dopaminergic neurons in the substantia nigra. In WT mice, however, the PFF induced only mild behavioral abnormalities, intestinal inflammation, α-synuclein deposition, and glial activation, without significant changes in microbiota and dopaminergic neurons. Our results reveal the possibility of α-synuclein aggregates binding to the intestinal mucosa and modeling PD in mice. This study may shed light on the investigation and early intervention of the gut-origin hypothesis in neurodegenerative diseases.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Uptake and inflammation of α-synuclein aggregates in intestinal mucosa-associated cell models.
Fig. 2: α-Synuclein aggregates produced inflammation and glial cell activation in an ex vivo intestinal organ culture system.
Fig. 3: Effects of α-synuclein aggregates on the colon in the acute coloclysis model.
Fig. 4: α-Synuclein aggregates induced behavioral disorders in the regular coloclysis model.
Fig. 5: α-Synuclein aggregates induced PD pathology in the intestine of the regular coloclysis model.
Fig. 6: Modification of cytokines and activation of macrophages in the intestine of WT and A53T mice.
Fig. 7: PFF induced the aggregation of endogenous α-synuclein in the brain of the regular coloclysis model.
Fig. 8: PFF induced microglial activation in the brain and the loss of TH neurons in the SNpc in the regular coloclysis model.
Fig. 9: α-Synuclein aggregates induced microbial imbalance in the regular coloclysis model.

Similar content being viewed by others

References

  1. Kalia LV, Lang AE. Parkinson’s disease. Lancet. 2015;386:896–912.

    Article  CAS  PubMed  Google Scholar 

  2. Paulus W, Jellinger K. The neuropathologic basis of different clinical subgroups of Parkinson’s disease. J Neuropathol Exp Neurol. 1991;50:743–55.

    Article  CAS  PubMed  Google Scholar 

  3. Gibb WR, Lees AJ. Anatomy, pigmentation, ventral and dorsal subpopulations of the substantia nigra, and differential cell death in Parkinson’s disease. J Neurol Neurosurg Psychiatry. 1991;54:388–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Vidailhet M. Parkinson disease—symptoms and treatments. Nat Rev Neurol. 2011;7:70–2.

    Article  CAS  PubMed  Google Scholar 

  5. Braak H, Ghebremedhin E, Rüb U, Bratzke H, Del Tredici K. Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res. 2004;318:121–34.

    Article  PubMed  Google Scholar 

  6. Dogra N, Mani RJ, Katare DP. The gut-brain axis: two ways signaling in Parkinson’s disease. Cell Mol Neurobiol. 2022;42:315–32.

    Article  CAS  PubMed  Google Scholar 

  7. Challis C, Hori A, Sampson TR, Yoo BB, Challis RC, Hamilton AM, et al. Gut-seeded α-synuclein fibrils promote gut dysfunction and brain pathology specifically in aged mice. Nat Neurosci. 2020;23:327–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Holmqvist S, Chutna O, Bousset L, Aldrin-Kirk P, Li W, Björklund T, et al. Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats. Acta Neuropathol. 2014;128:805–20.

    Article  PubMed  Google Scholar 

  9. Kim S, Kwon SH, Kam TI, Panicker N, Karuppagounder SS, Lee S, et al. Transneuronal propagation of pathologic α-synuclein from the gut to the brain models Parkinson’s disease. Neuron. 2019;103:627–.e7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Park S, Kim J, Chun J, Han K, Soh H, Kang EA, et al. Patients with inflammatory bowel disease are at an increased risk of Parkinson’s disease: a South Korean nationwide population-based study. J Clin Med. 2019;8:1191.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Pan-Montojo F, Anichtchik O, Dening Y, Knels L, Pursche S, Jung R, et al. Progression of Parkinson’s disease pathology is reproduced by intragastric administration of rotenone in mice. PLoS One. 2010;5:e8762.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Kishimoto Y, Zhu W, Hosoda W, Sen JM, Mattson MP. Chronic mild gut inflammation accelerates brain neuropathology and motor dysfunction in α-synuclein mutant mice. Neuromol Med. 2019;21:239–49.

    Article  CAS  Google Scholar 

  13. Sampson TR, Debelius JW, Thron T, Janssen S, Shastri GG, Ilhan ZE, et al. Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson’s disease. Cell. 2016;167:1469–.e12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Pellegrini C, D’Antongiovanni V, Miraglia F, Rota L, Benvenuti L, Di Salvo C, et al. Enteric α-synuclein impairs intestinal epithelial barrier through caspase-1-inflammasome signaling in Parkinson’s disease before brain pathology. NPJ Parkinsons Dis. 2022;8:9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Houser MC, Tansey MG. The gut-brain axis: is intestinal inflammation a silent driver of Parkinson’s disease pathogenesis? NPJ Parkinsons Dis. 2017;3:3.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Oppong GO, Rapsinski GJ, Tursi SA, Biesecker SG, Klein-Szanto AJP, Goulian M, et al. Biofilm-associated bacterial amyloids dampen inflammation in the gut: oral treatment with curli fibres reduces the severity of hapten-induced colitis in mice. NPJ Biofilms Microbiomes. 2015;1:15019.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Sampson TR, Challis C, Jain N, Moiseyenko A, Ladinsky MS, Shastri GG, et al. A gut bacterial amyloid promotes a-synuclein aggregation and motor impairment in mice. Elife. 2020;9:1–19.

    Article  Google Scholar 

  18. Masuda-Suzukake M, Nonaka T, Hosokawa M, Oikawa T, Arai T, Akiyama H, et al. Prion-like spreading of pathological α-synuclein in brain. Brain. 2013;136:1128–38.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Paslawski W, Andreasen M, Nielsen SB, Lorenzen N, Thomsen K, Kaspersen JD, et al. High stability and cooperative unfolding of α-synuclein oligomers. Biochemistry. 2014;53:6252–63.

    Article  CAS  PubMed  Google Scholar 

  20. Marczynski M, Rickert CA, Semerdzhiev SA, van Dijk WR, Segers-Nolten IMJ, Claessens MMAE, et al. α-Synuclein penetrates mucin hydrogels despite its mucoadhesive properties. Biomacromolecules. 2019;20:4332–44.

    Article  CAS  PubMed  Google Scholar 

  21. Lohmann S, Bernis ME, Tachu BJ, Ziemski A, Grigoletto J, Tamgüney G. Oral and intravenous transmission of α-synuclein fibrils to mice. Acta Neuropathol. 2019;138:515–33.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Killinger BA, Labrie V. Vertebrate food products as a potential source of prion-like α-synuclein. NPJ Parkinsons Dis. 2017;3:33.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Lerner A. The intestinal luminal sources of α-synuclein: a gastroenterologist perspective. Nutr Rev. 2022;80:282–93.

    Article  PubMed  Google Scholar 

  24. Hu H, Wang Q, Du J, Liu Z, Ding Y, Xue H, et al. Aha1 exhibits distinctive dynamics behavior and chaperone-like activity. Molecules. 2021;26:1943.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Barlow-Anacker AJ, Erickson CS, Epstein ML, Gosain A. Immunostaining to visualize murine enteric nervous system development. J Visual Exp. 2015;29:e52716.

    Google Scholar 

  26. Giasson BI, Duda JE, Quinn SM, Zhang B, Trojanowski JQ, Lee VMY. Neuronal α-synucleinopathy with severe movement disorder in mice expressing A53T human α-synuclein. Neuron. 2002;34:521–33.

    Article  CAS  PubMed  Google Scholar 

  27. Yissachar N, Zhou Y, Ung L, Lai NY, Mohan JF, Ehrlicher A, et al. An intestinal organ culture system uncovers a role for the nervous system in microbe-immune crosstalk. Cell. 2017;168:1135–e12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Wu Q, Yang X, Zhang Y, Zhang L, Feng L. Chronic mild stress accelerates the progression of Parkinson’s disease in A53T α-synuclein transgenic mice. Exp Neurol. 2016;285:61–71.

    Article  CAS  PubMed  Google Scholar 

  29. Caporaso JG, Kuczynski J, Stombaugh J, Bittinger K, Bushman FD, Costello EK, et al. QIIME allows analysis of high-throughput community sequencing data. Nat Methods. 2010;7:335–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Rognes T, Flouri T, Nichols B, Quince C, Mahé F. VSEARCH: a versatile open source tool for metagenomics. PeerJ. 2016;4:e2584.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Wang Q, Garrity GM, Tiedje JM, Cole JR. Naïve Bayesian classifier for rapid assignment of rRNA sequences into the new bacterial taxonomy. Appl Environ Microbiol. 2007;73:5261–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Douglas GM, Maffei VJ, Zaneveld JR, Yurgel SN, Brown JR, Taylor CM, et al. PICRUSt2 for prediction of metagenome functions. Nat Biotechnol. 2020;38:685–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Antunes F, Andrade F, Araújo F, Ferreira D, Sarmento B. Establishment of a triple co-culture in vitro cell models to study intestinal absorption of peptide drugs. Eur J Pharm Biopharm. 2013;83:427–35.

    Article  CAS  PubMed  Google Scholar 

  34. Van Den Berge N, Ferreira N, Mikkelsen TW, Alstrup AKO, Tamgüney G, Karlsson P, et al. Ageing promotes pathological alpha-synuclein propagation and autonomic dysfunction in wild-type rats. Brain. 2021;144:1853–68.

    Article  PubMed  Google Scholar 

  35. Coskuner O, Wise-Scira O. Structures and free energy landscapes of the A53T mutant-type α-synuclein protein and impact of A53T mutation on the structures of the wild-type α-synuclein protein with dynamics. ACS Chem Neurosci. 2013;4:1101–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Yemula N, Dietrich C, Dostal V, Hornberger M. Parkinson’s disease and the gut: symptoms, nutrition, and microbiota. J Parkinsons Dis. 2021;11:1491–505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Olanow CW, Brundin P. Parkinson’s disease and alpha synuclein: is Parkinson’s disease a prion-like disorder? Mov Disord. 2013;28:31–40.

    Article  CAS  PubMed  Google Scholar 

  38. Wittung-Stafshede P. Gut power: modulation of human amyloid formation by amyloidogenic proteins in the gastrointestinal tract. Curr Opin Struct Biol. 2022;72:33–8.

    Article  CAS  PubMed  Google Scholar 

  39. Banerjee A, Qi J, Gogoi R, Wong J, Mitragotri S. Role of nanoparticle size, shape and surface chemistry in oral drug delivery. J Control Release. 2016;238:176–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Lee SB, Park SM, Ahn KJ, Chung KC, Paik SR, Kim J. Identification of the amino acid sequence motif of α-synuclein responsible for macrophage activation. Biochem Biophys Res Commun. 2009;381:39–43.

    Article  CAS  PubMed  Google Scholar 

  41. Gorecki AM, Anyaegbu CC, Anderton RS. TLR2 and TLR4 in Parkinson’s disease pathogenesis: the environment takes a toll on the gut. Transl Neurodegener. 2021;10:47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Friedland RP, Chapman MR. The role of microbial amyloid in neurodegeneration. PLoS Pathog. 2017;13:e1006654.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Song S, Liu J, Zhang F, Hong JS. Norepinephrine depleting toxin DSP-4 and LPS alter gut microbiota and induce neurotoxicity in α-synuclein mutant mice. Sci Rep. 2020;10:15054.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Ahn EH, Liu X, Alam AM, Kang SS, Ye K. Helicobacter hepaticus augmentation triggers dopaminergic degeneration and motor disorders in mice with Parkinson’s disease. Mol Psychiatry. 2023;28:1337–50.

    Article  CAS  PubMed  Google Scholar 

  45. Xie Z, Zhang M, Luo Y, Jin D, Guo X, Yang W, et al. Healthy human fecal microbiota transplantation into mice attenuates MPTP-induced neurotoxicity via AMPK/SOD2 pathway. Aging Dis. 2023. https://doi.org/10.14336/AD.2023.0309.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Wallen ZD, Demirkan A, Twa G, Cohen G, Dean MN, Standaert DG, et al. Metagenomics of Parkinson’s disease implicates the gut microbiome in multiple disease mechanisms. Nat Commun. 2022;13:6958.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Gerhardt S, Mohajeri M. Changes of colonic bacterial composition in parkinson’s disease and other neurodegenerative diseases. Nutrients. 2018;10:708.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Zhang Y, He X, Qian Y, Xu S, Mo C, Yan Z, et al. Plasma branched-chain and aromatic amino acids correlate with the gut microbiota and severity of Parkinson’s disease. NPJ Parkinsons Dis. 2022;8:48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Shen T, Yue Y, He T, Huang C, Qu B, Lv W, et al. The association between the gut microbiota and parkinson’s disease, a meta-analysis. Front Aging Neurosci. 2021;13:636545.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Nishiwaki H, Hamaguchi T, Ito M, Ishida T, Maeda T, Kashihara K, et al. Short-chain fatty acid-producing gut microbiota is decreased in parkinson’s disease but not in rapid-eye-movement sleep behavior disorder. mSystems. 2020;5:e00797–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Baldini F, Hertel J, Sandt E, Thinnes CC, Neuberger-Castillo L, Pavelka L, et al. Parkinson’s disease-associated alterations of the gut microbiome predict disease-relevant changes in metabolic functions. BMC Biol. 2020;18:62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Emin D, Zhang YP, Lobanova E, Miller A, Li X, Xia Z, et al. Small soluble α-synuclein aggregates are the toxic species in Parkinson’s disease. Nat Commun. 2022;13:5512.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This study was supported by grants from the National Science & Technology Major Project “Key New Drug Creation and Manufacturing Program”, China (2018ZX09711002–003–013), and the Scientific Innovation Project of the Chinese Academy of Sciences (XDA12040304 and XDA12040216). This project was supported by the Shanghai Committee of Science and Technology, China (18DZ2290200), and the grants from National Natural Science Foundation of China (No. 82104140, 32171220).

Author information

Author notes

  1. These authors contributed equally: Ze-xian Yang, Yu Zhang.

Authors and Affiliations

  1. CAS Key Laboratory of Receptor Research, Center for Neurological and Psychiatric Research and Drug Discovery (CNPRDD), Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, China

    Ze-xian Yang, Yu Zhang, Qing Wang, Lei Zhang, Yi-fei Liu, Ye Zhang, Yu Ren & Lin-yin Feng

  2. University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China

    Ze-xian Yang, Qing Wang, Ye Zhang, Nai-xia Zhang & Lin-yin Feng

  3. Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, 264117, China

    Yu Zhang & Hui-wen Gao

  4. Analytical Research Center for Organic and Biological Molecules, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China

    Chen Zhou & Nai-xia Zhang

  5. Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China

    Hui-wen Gao

Authors
  1. Ze-xian Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yu Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Qing Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lei Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yi-fei Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ye Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yu Ren
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Chen Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hui-wen Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Nai-xia Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Lin-yin Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

LYF, ZXY, and YZ designed the experiments. ZXY and YZ performed the experiments. QW, LZ, YFL, and CZ performed some of the experiments. YZ, YR, and HWG assisted with the experiments. ZXY and YZ wrote the manuscript. LYF, NXZ and YZ supervised the study.

Corresponding authors

Correspondence to Yu Zhang, Nai-xia Zhang or Lin-yin Feng.

Ethics declarations

Competing interests

The authors declare no competing interests.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yang, Zx., Zhang, Y., Wang, Q. et al. Addition of α-synuclein aggregates to the intestinal environment recapitulates Parkinsonian symptoms in model systems. Acta Pharmacol Sin 45, 36–51 (2024). https://doi.org/10.1038/s41401-023-01150-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41401-023-01150-2

Keywords

Search

Advanced search

Quick links