Abstract

Though emerging evidence indicates that the pathogenesis of Parkinson’s disease is strongly correlated to the accumulation1,2 and transmission3,4 of α-synuclein (α-syn) aggregates in the midbrain, no anti-aggregation agents have been successful at treating the disease in the clinic. Here, we show that graphene quantum dots (GQDs) inhibit fibrillization of α-syn and interact directly with mature fibrils, triggering their disaggregation. Moreover, GQDs can rescue neuronal death and synaptic loss, reduce Lewy body and Lewy neurite formation, ameliorate mitochondrial dysfunctions, and prevent neuron-to-neuron transmission of α-syn pathology provoked by α-syn preformed fibrils5,6. We observe, in vivo, that GQDs penetrate the blood–brain barrier and protect against dopamine neuron loss induced by α-syn preformed fibrils, Lewy body/Lewy neurite pathology and behavioural deficits.

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References

  1. 1.

    Dawson, T. M. & Dawson, V. L. Molecular pathways of neurodegeneration in Parkinson’s disease. Science 302, 819–822 (2003).

  2. 2.

    Spillantini, M. G. et al. Alpha-synuclein in Lewy bodies. Nature 388, 839–840 (1997).

  3. 3.

    Li, J. Y. et al. Lewy bodies in grafted neurons in subjects with Parkinson’s disease suggest host-to-graft disease propagation. Nat. Med. 14, 501–503 (2008).

  4. 4.

    Desplats, P. et al. Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein. Proc. Natl Acad. Sci. USA 106, 13010–13015 (2009).

  5. 5.

    Volpicelli-Daley, L. A. et al. Exogenous alpha-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death. Neuron 72, 57–71 (2011).

  6. 6.

    Luk, K. C. et al. Pathological alpha-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science 338, 949–953 (2012).

  7. 7.

    Varela, L., Bell, C. H., Armitage, J. P. & Redfield, C. 1H, 13C and 15N resonance assignments for the response regulator CheY3 from Rhodobacter sphaeroides. Biomol. NMR Assign. 10, 373–378 (2016).

  8. 8.

    Bodner, C. R., Dobson, C. M. & Bax, A. Multiple tight phospholipid-binding modes of alpha-synuclein revealed by solution NMR spectroscopy. J. Mol. Biol. 390, 775–790 (2009).

  9. 9.

    Tuttle, M. D. et al. Solid-state NMR structure of a pathogenic fibril of full-length human alpha-synuclein. Nat. Struct. Mol. Biol. 23, 409–415 (2016).

  10. 10.

    Giasson, B. I., Murray, I. V. J., Trojanowski, J. Q. & Lee, V. M. Y. A hydrophobic stretch of 12 amino acid residues in the middle of alpha-synuclein is essential for filament assembly. J. Biol. Chem. 276, 2380–2386 (2001).

  11. 11.

    van Stokkum, I. H., Spoelder, H. J., Bloemendal, M., van Grondelle, R. & Groen, F. C. Estimation of protein secondary structure and error analysis from circular dichroism spectra. Anal. Biochem 191, 110–118 (1990).

  12. 12.

    Sreerama, N. & Woody, R. W. Estimation of protein secondary structure from circular dichroism spectra: comparison of CONTIN, SELCON, and CDSSTR methods with an expanded reference set. Anal. Biochem. 287, 252–260 (2000).

  13. 13.

    Lin, M. T. & Beal, M. F. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443, 787–795 (2006).

  14. 14.

    Czupalla, C. J., Liebner, S. & Devraj, K. In vitro models of the blood–brain barrier. Methods Mol. Biol. 1135, 415–437 (2014).

  15. 15.

    Lee, M. K. et al. Human α-synuclein-harboring familial Parkinson’s disease-linked Ala-53→Thr mutation causes neurodegenerative disease with α-synuclein aggregation in transgenic mice. Proc. Natl Acad. Sci. USA 99, 8968–8973 (2002).

  16. 16.

    Brahmachari, S. et al. Activation of tyrosine kinase c-Abl contributes to α-synuclein-induced neurodegeneration. J. Clin. Invest. 126, 2970–2988 (2016).

  17. 17.

    Li, Q. et al. Modulating Aβ33–42 peptide assembly by graphene oxide. Chem. Eur. J. 20, 7236–7240 (2014).

  18. 18.

    Mahmoudi, M., Akhavan, O., Ghavami, M., Rezaee, F. & Ghiasi, S. M. A. Graphene oxide strongly inhibits amyloid beta fibrillation. Nanoscale 4, 7322–7325 (2012).

  19. 19.

    Liu, Y. et al. Graphene quantum dots for the inhibition of beta amyloid aggregation. Nanoscale 7, 19060–19065 (2015).

  20. 20.

    Yang, Z. X. et al. Destruction of amyloid fibrils by graphene through penetration and extraction of peptides. Nanoscale 7, 18725–18737 (2015).

  21. 21.

    Volpicelli-Daley, L. A., Luk, K. C. & Lee, V. M. Addition of exogenous alpha-synuclein preformed fibrils to primary neuronal cultures to seed recruitment of endogenous alpha-synuclein to Lewy body and Lewy neurite-like aggregates. Nat. Protoc. 9, 2135–2146 (2014).

  22. 22.

    Delaglio, F. et al. NMRPipe: a multidimensional spectral processing system based on UNIX pipes. J. Biomol. NMR 6, 277–293 (1995).

  23. 23.

    Lee, W., Tonelli, M. & Markley, J. L. NMRFAM-SPARKY: enhanced software for biomolecular NMR spectroscopy. Bioinformatics 31, 1325–1327 (2015).

  24. 24.

    Abraham, M. J. et al. GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX 1-2, 19–25 (2015).

  25. 25.

    Mackerell, A. D.Jr., Feig, M. & Brooks, C. L. III Extending the treatment of backbone energetics in protein force fields: limitations of gas-phase quantum mechanics in reproducing protein conformational distributions in molecular dynamics simulations. J. Comput. Chem. 25, 1400–1415 (2004).

  26. 26.

    Yu, W., He, X., Vanommeslaeghe, K. & MacKerell, A. D. Jr. Extension of the CHARMM General Force Field to sulfonyl-containing compounds and its utility in biomolecular simulations. J. Comput. Chem. 33, 2451–2468 (2012).

  27. 27.

    Lee, M. K. et al. Human α-synuclein-harboring familial Parkinson’s disease-linked Ala-53→Thr mutation causes neurodegenerative disease with α-synuclein aggregation in transgenic mice. Proc. Natl Acad. Sci. USA 99, 8968–8973 (2002).

  28. 28.

    Peelaerts, W. et al. α-Synuclein strains cause distinct synucleinopathies after local and systemic administration. Nature 522, 340–344 (2015).

  29. 29.

    Mao, X. et al. Pathological α-synuclein transmission initiated by binding lymphocyte-activation gene 3. Science 353, aah3374 (2016).

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Acknowledgements

This work was supported by BIOGRAPHENE Inc. and an NRF (National Research Foundation of Korea) grant funded by the Korean government (NRF-2014H1A2A1016534-Global PhD Fellowship Program, NRF-2011-357-C00119) and grants from NIH/NINDS NS082205, NIH/NINDS NS098006 and NIH/NINDS NS38377 from the Morris K. Udall Parkinson’s Disease Research Center. This work was made possible by support from the Johns Hopkins Medicine Discovery Fund. The authors acknowledge joint participation by the Diana Helis Henry Medical Research Foundation and the Adrienne Helis Malvin Medical Research Foundation through direct engagement in the continuous active conduct of medical research in conjunction with The Johns Hopkins Hospital and the Johns Hopkins University School of Medicine and the Foundation’s Parkinson’s Disease Program H-1, H-2013 and M-2014. The authors extend their sincere gratitude to H. Lee of Ewha Womans University for discussions and helpful advice.

Author information

Author notes

  1. These authors contributed equally: Donghoon Kim, Je Min Yoo.

Affiliations

  1. Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

    • Donghoon Kim
    • , Heehong Hwang
    • , Su Hyun Lee
    • , Seung Pil Yun
    • , Seulah Choi
    • , Sang Ho Kwon
    • , Saebom Lee
    • , Seung-Hwan Kwon
    • , Sangjune Kim
    •  & Han Seok Ko
  2. Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

    • Donghoon Kim
    • , Su Hyun Lee
    • , Seung Pil Yun
    • , Saebom Lee
    • , Seung-Hwan Kwon
    • , Sangjune Kim
    •  & Han Seok Ko
  3. Department of Chemistry, College of Natural Science, Seoul National University, Seoul, Republic of Korea

    • Je Min Yoo
    • , Myung Jin Park
    • , MinJun Lee
    • , Seokmin Shin
    •  & Byung Hee Hong
  4. Department of Neuroscience and Physiology, Interdisciplinary Program in Neuroscience, Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Republic of Korea

    • Heehong Hwang
    •  & Sung Joong Lee
  5. Inter-University Semiconductor Research Centre, Seoul National University, Seoul, Republic of Korea

    • Junghee Lee
    •  & Byung Hee Hong
  6. Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA, USA

    • Seung Pil Yun
    •  & Han Seok Ko
  7. The Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    • Yong Joo Park
    •  & Seulki Lee
  8. Institute for Protein Research, Osaka University, Yamadaoka, Osaka, Japan

    • Misaki Kinoshita
    •  & Young-Ho Lee
  9. School of Chemical and Biological Engineering, College of Engineering, Seoul National University, Seoul, Republic of Korea

    • Seung R. Paik
  10. The Centre for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    • Seulki Lee
  11. Diana Helis Henry Medical Research Foundation, New Orleans, LA, USA

    • Han Seok Ko

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Contributions

B.H.H. and H.S.K. supervised the project. B.H.H. and J.M.Y. conceived the original idea of using GQDs for Parkinson’s disease. B.H.H., H.S.K., D.K. and J.M.Y. contributed to the study design. D.K., J.M.Y., H.H., S.H.L., S.P.Y., M.J.P., S.C., S.H.K., S.L., S.-H.K., S.K., Y.J.P., S.J.L. and S.L. contributed to overall data collection and interpretation. J.L., M.K., Y.-H.L. and S.R.P. contributed to NMR data collection and interpretation. M.L. and S.S. contributed to MD simulation and analysis. J.M.Y., J.L., S.R.P. and B.H.H. contributed to CD measurements and analysis. D.K., J.M.Y., S.H.L., B.H.H. and H.S.K wrote the paper. All authors discussed and commented on the manuscript.

Competing interests

The authors declare no competing interests.

Corresponding authors

Correspondence to Byung Hee Hong or Han Seok Ko.

Supplementary information

  1. Supplementary Information

    Supplementary Methods, Supplementary Table 1, Supplementary Figures 1–13, Supplementary References

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DOI

https://doi.org/10.1038/s41565-018-0179-y