SpringerLink
Log in

A core-satellite-like nanoassembly reverses a decisive tyrosine hydroxylase loss in degenerative dopaminergic neurons

  • Research Article
  • Published:
Nano Research Aims and scope Submit manuscript

Abstract

In recent years, neurodegenerative diseases, such as Parkinson’s or Alzheimer’s diseases, are rapidly rising in prevalence. The main hallmark of Parkinson’s disease is the falling levels of neurotransmitter dopamine in the mid-brain with dopaminergic neurons losing. Typical therapeutic solutions, including drugs, deep brain stimulation, and cell transplantation, can only alleviate the symptoms of Parkinson’s disease. It is a tremendous challenge to reverse the function degeneration of the crucial dopaminergic neurons. Herein, we develop a core-satellite-like nanoassembly (PDA-AFn (by integrating polydopamine nanoparticles and apoferritin)) to raise the expression of tyrosine hydroxylase (TH), a rate-limiting enzyme in the formation of the dopamine. Both components in the nanoassembly could cooperate with each other, not only elaborately regulate the iron homeostasis and redox microenvironment, but also utilize excessive reactive oxygen species (ROS) and iron ions in the damaged neurons to supply extra dopamine and enhance TH activity, and consequently restore the function of the degenerated neurons. Remarkably, the nanoassembly-treatment relieves the dyskinesia and dramatical increases the tyrosine hydroxylase and dopamine level in the midbrain of Parkinson’s disease model mice. It is an explicit yet inspiring advance in treatment of the neurodegeneration.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Germany)

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Lotharius, J.; Brundin, P. Pathogenesis of Parkinson’s disease: Dopamine, vesicles and α-synuclein. Nat. Rev. Neurosci. 2002, 3, 932–942.

    CAS  Google Scholar 

  2. da Silva, J. A.; Tecuapetla, F.; Paixão, V.; Costa, R. M. Dopamine neuron activity before action initiation gates and invigorates future movements. Nature 2018, 554, 244–248.

    Google Scholar 

  3. Nobili, A.; Latagliata, E. C.; Viscomi, M. T.; Cavallucci, V.; Cutuli, D.; Giacovazzo, G.; Krashia, P.; Rizzo, F. R.; Marino, R.; Federici, M. et al. Dopamine neuronal loss contributes to memory and reward dysfunction in a model of Alzheimer’s disease. Nat. Commun. 2017, 8, 14727.

    CAS  Google Scholar 

  4. Kalia, L. V.; Lang, A. E. Parkinson’s disease. Lancet 2015, 386, 896–912.

    CAS  Google Scholar 

  5. Chaudhuri, K. R.; Schapira, A. H. V. Non-motor symptoms of Parkinson’s disease: Dopaminergic pathophysiology and treatment. Lancet Neurol. 2009, 8, 464–474.

    CAS  Google Scholar 

  6. Kim, T.; Kim, H. J.; Choi, W.; Lee, Y. M.; Pyo, J. H.; Lee, J.; Kim, J.; Kim, J.; Kim, J. H.; Kim, C. et al. Deep brain stimulation by blood-brain-barrier-crossing piezoelectric nanoparticles generating current and nitric oxide under focused ultrasound. Nat. Biomed. Eng. 2023, 7, 149–163.

    CAS  Google Scholar 

  7. Howe, M. W.; Dombeck, D. A. Rapid signalling in distinct dopaminergic axons during locomotion and reward. Nature 2016, 535, 505–510.

    CAS  Google Scholar 

  8. Lee, T.; Cai, L. X.; Lelyveld, V. S.; Hai, A.; Jasanoff, A. Molecular-level functional magnetic resonance imaging of dopaminergic signaling. Science 2014, 344, 533–535.

    CAS  Google Scholar 

  9. Tiklová, K.; Björklund, Å. K.; Lahti, L.; Fiorenzano, A.; Nolbrant, S.; Gillberg, L.; Volakakis, N.; Yokota, C.; Hilscher, M. M.; Hauling, T. et al. Single-cell RNA sequencing reveals midbrain dopamine neuron diversity emerging during mouse brain development. Nat. Commun. 2019, 10, 581.

    Google Scholar 

  10. Feng, P. J.; Chen, Y. L.; Zhang, L.; Qian, C. G.; **ao, X. Z.; Han, X.; Shen, Q. D. Near-infrared fluorescent nanoprobes for revealing the role of dopamine in drug addiction. ACS Appl. Mater. Interfaces 2018, 10, 4359–4368.

    CAS  Google Scholar 

  11. Raza, C.; Anjum, R.; Shakeel, N. U. A. Parkinson’s disease: Mechanisms, translational models and management strategies. Life Sci. 2019, 226, 77–90.

    CAS  Google Scholar 

  12. Dehay, B.; Bourdenx, M.; Gorry, P.; Przedborski, S.; Vila, M.; Hunot, S.; Singleton, A.; Olanow, C. W.; Merchant, K. M.; Bezard, E. et al. Targeting α-synuclein for treatment of Parkinson’s disease: Mechanistic and therapeutic considerations. Lancet Neurol. 2015, 14, 855–866.

    CAS  Google Scholar 

  13. de Bie, R. M. A.; Clarke, C. E.; Espay, A. J.; Fox, S. H.; Lang, A. E. Initiation of pharmacological therapy in Parkinson’s disease: When, why, and how. Lancet Neurol. 2020, 19, 452–461.

    CAS  Google Scholar 

  14. Ogawa, N. Levodopa and dopamine agonists in the treatment of Parkinson’s disease: Advantages and disadvantages. Eur. Neurol. 1994, 34, 20–28.

    Google Scholar 

  15. Kriks, S.; Shim, J. W.; Piao, J.; Ganat, Y. M.; Wakeman, D. R.; **e, Z.; Carrillo-Reid, L.; Auyeung, G.; Antonacci, C.; Buch, A. et al. Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson’s disease. Nature 2011, 480, 547–551.

    CAS  Google Scholar 

  16. Kikuchi, T.; Morizane, A.; Doi, D.; Magotani, H.; Onoe, H.; Hayashi, T.; Mizuma, H.; Takara, S.; Takahashi, R.; Inoue, H. et al. Human iPS cell-derived dopaminergic neurons function in a primate Parkinson’s disease model. Nature 2017, 548, 592–596.

    CAS  Google Scholar 

  17. Zhang, Z. R.; Wang, F. Y.; Song, M. J. The cell repair research of spinal cord injury: A review of cell transplantation to treat spinal cord injury. J. Neurorestoratol. 2019, 7, 55–62.

    CAS  Google Scholar 

  18. Rao, F. W.; Zhang, L.; Wessel, J.; Zhang, K. X.; Wen, G.; Kennedy, B. P.; Rana, B. K.; Das, M.; Rodriguez-Flores, J. L.; Smith, D. W. et al. Tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis: Discovery of common human genetic variants governing transcription, autonomic activity, and blood pressure in vivo. Circulation 2007, 116, 993–1006.

    CAS  Google Scholar 

  19. Morales, M.; Margolis, E. B. Ventral tegmental area: Cellular heterogeneity, connectivity and behaviour. Nat. Rev. Neurosci. 2017, 18, 73–85.

    CAS  Google Scholar 

  20. Lammel, S.; Lim, B. K.; Malenka, R. C. Reward and aversion in a heterogeneous midbrain dopamine system. Neuropharmacology 2014, 76, 351–359.

    CAS  Google Scholar 

  21. Jiao, S. S.; Gurevich, V.; Wolff, J. A. Long-term correction of rat model of Parkinson’s disease by gene therapy. Nature 1993, 362, 450–453.

    CAS  Google Scholar 

  22. Du, X. Y.; Iacovitti, L. Multiple signaling pathways direct the initiation of tyrosine hydroxylase gene expression in cultured brain neurons. Mol. Brain Res. 1997, 50, 1–8.

    CAS  Google Scholar 

  23. Du, X. Y.; Stull, N. D.; Iacovitti, L. Brain-derived neurotrophic factor works coordinately with partner molecules to initiate tyrosine hydroxylase expression in striatal neurons. Brain Res. 1995, 680, 229–233.

    CAS  Google Scholar 

  24. Tavakol, S.; Musavi, S. M. M.; Tavakol, B.; Hoveizi, E.; Ai, J.; Rezayat, S. M. Noggin along with a self-assembling peptide nanofiber containing long motif of laminin induces tyrosine hydroxylase gene expression. Mol. Neurobiol. 2017, 54, 4609–4616.

    CAS  Google Scholar 

  25. Zhao, D.; Feng, P. J.; Liu, J. H.; Dong, M.; Shen, X. Q.; Chen, Y. X.; Shen, Q. D. Electromagnetized -nanoparticle-modulated neural plasticity and recovery of degenerative dopaminergic neurons in the mid-brain. Adv. Mater. 2020, 32, 2003800.

    CAS  Google Scholar 

  26. El Mestikawy, S.; Glowinski, J.; Hamon, M. Tyrosine hydroxylase activation in depolarized dopaminergic terminals-involvement of Ca2+-dependent phosphorylation. Nature 1983, 302, 830–832.

    CAS  Google Scholar 

  27. Haycock, J. W.; Ahn, N. G.; Cobb, M. H.; Krebs, E. G. ERK1 and ERK2, two microtubule-associated protein 2 kinases, mediate the phosphorylation of tyrosine hydroxylase at serine-31 in situ. Proc. Natl. Acad. Sci. USA 1992, 89, 2365–2369.

    CAS  Google Scholar 

  28. Burbulla, L. F.; Song, P. P.; Mazzulli, J. R.; Zampese, E.; Wong, Y. C.; Jeon, S.; Santos, D. P.; Blanz, J.; Obermaier, C. D.; Strojny, C. et al. Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson’s disease. Science 2017, 357, 1255–1261.

    CAS  Google Scholar 

  29. McCormack, A. L.; Atienza, J. G.; Johnston, L. C.; Andersen, J. K.; Vu, S.; Di Monte, D. A. Role of oxidative stress in paraquat-induced dopaminergic cell degeneration. J. Neurochem. 2005, 93, 1030–1037.

    CAS  Google Scholar 

  30. Kim, G. H.; Kim, J. E.; Rhie, S. J.; Yoon, S. The role of oxidative stress in neurodegenerative diseases. Exp. Neurobiol. 2015, 24, 325–340.

    Google Scholar 

  31. Dela Cruz, C. P.; Revilla, E.; Venero, J. L.; Ayala, A.; Cano, J.; MacHado, A. Oxidative inactivation of tyrosine hydroxylase in substantia nigra of aged rat. Free Radical Biol. Med. 1996, 20, 53–61.

    CAS  Google Scholar 

  32. Rostrup, M.; Fossbakk, A.; Hauge, A.; Kleppe, R.; Gnaiger, E.; Haavik, J. Oxygen dependence of tyrosine hydroxylase. Amino Acids 2008, 34, 455–464.

    CAS  Google Scholar 

  33. Rodríguez-Gómez, J. A.; Venero, J. L.; Vizuete, M. L.; Cano, J.; Machado, A. Deprenyl induces the tyrosine hydroxylase enzyme in the rat dopaminergic nigrostriatal system. Mol. Brain Res. 1997, 46, 31–38.

    Google Scholar 

  34. Knörle, R. Neuromelanin in Parkinson’s Disease: From Fenton reaction to calcium signaling. Neurotox. Res. 2018, 33, 515–522.

    Google Scholar 

  35. Hirsch, E. C.; Brandel, J. P.; Galle, P.; Javoyagid, F.; Agid, Y. Iron and aluminum increase in the Substantia Nigra of patients with Parkinson’s disease: An X-ray-Microanalysis. J. Neurochem. 1991, 56, 446–451.

    CAS  Google Scholar 

  36. Frantom, P. A.; Seravalli, J.; Ragsdale, S. W.; Fitzpatrick, P. F. Reduction and oxidation of the active site iron in tyrosine hydroxylase: Kinetics and specificity. Biochemistry 2006, 45, 2372–2379.

    CAS  Google Scholar 

  37. Zhou, J.; Zhang, Z. Y.; Joseph, J.; Zhang, X. C.; Ferdows, B. E.; Patel, D. N.; Chen, W.; Banfi, G.; Molinaro, R.; Cosco, D. et al. Biomaterials and nanomedicine for bone regeneration: Progress and future prospects. Exploration 2021, 1, 20210011.

    Google Scholar 

  38. Zhang, Y. Y.; Tang, Z. W.; Wang, J.; Wu, H.; Lin, C. T.; Lin, Y. H. Apoferritin nanoparticle: A novel and biocompatible carrier for enzyme immobilization with enhanced activity and stability. J. Mater. Chem. 2011, 21, 17468–17475.

    CAS  Google Scholar 

  39. Jutz, G.; van Rijn, P.; Miranda, B. S.; Böker, A. Ferritin: A versatile building block for bionanotechnology. Chem. Rev. 2015, 115, 1653–1701.

    CAS  Google Scholar 

  40. Zhang, N.; Yu, X. Q.; **e, J. X.; Xu, H. M. New insights into the role of ferritin in iron homeostasis and neurodegenerative diseases. Mol. Neurobiol. 2021, 58, 2812–2823.

    CAS  Google Scholar 

  41. Balla, G.; Jacob, H. S.; Balla, J.; Rosenberg, M.; Nath, K.; Apple, F.; Eaton, J. W.; Vercellotti, G. M. Ferritin: A cytoprotective antioxidant strategem of endothelium. J. Biol. Chem. 1992, 267, 18148–18153.

    CAS  Google Scholar 

  42. d’Ischia, M.; Napolitano, A.; Ball, V.; Chen, C. T.; Buehler, M. J. Polydopamine and eumelanin: From structure-property relationships to a unified tailoring strategy. Acc. Chem. Res. 2014, 47, 3541–3550.

    Google Scholar 

  43. Kang, K.; Choi, I. S.; Nam, Y. A biofunctionalization scheme for neural interfaces using polydopamine polymer. Biomaterials 2011, 32, 6374–6380.

    CAS  Google Scholar 

  44. Li, Y. W.; **e, Y. J.; Wang, Z.; Zang, N. Z.; Carniato, F.; Huang, Y. R.; Andolina, C. M.; Parent, L. R.; Ditri, T. B.; Walter, E. D. et al. Structure and function of iron-loaded synthetic melanin. ACS Nano 2016, 10, 10186–10194.

    CAS  Google Scholar 

  45. Zhang, Z. Y.; Zhou, J.; Liu, C.; Zhang, J. M.; Shibata, Y.; Kong, N.; Corbo, C.; Harris, M. B.; Tao, W. Emerging biomimetic nanotechnology in orthopedic diseases: Progress, challenges, and opportunities. Trends Chem. 2022, 4, 420–436.

    CAS  Google Scholar 

  46. Battaglini, M.; Marino, A.; Carmignani, A.; Tapeinos, C.; Cauda, V.; Ancona, A.; Garino, N.; Vighetto, V.; La Rosa, G.; Sinibaldi, E. et al. Polydopamine nanoparticles as an organic and biodegradable multitasking tool for neuroprotection and remote neuronal stimulation. ACS Appl. Mater. Interfaces. 2020, 12, 35782–35798.

    CAS  Google Scholar 

  47. Bao, X. F.; Zhao, J. H.; Sun, J.; Hu, M.; Yang, X. R. Polydopamine nanoparticles as efficient scavengers for reactive oxygen species in periodontal disease. ACS Nano 2018, 12, 8882–8892.

    CAS  Google Scholar 

  48. Chasteen, N. D.; Harrison, P. M. Mineralization in ferritin: An efficient means of iron storage. J. Struct. Biol. 1999, 126, 182–194.

    CAS  Google Scholar 

  49. Harrison, P. M. The structure of apoferritin: Molecular size, shape and symmetry from X-ray data. J. Mol. Biol. 1963, 6, 404–422.

    CAS  Google Scholar 

  50. Aguilera-Garrido, A.; Del Castillo-Santaella, T.; Yang, Y.; Galisteo-González, F.; Gálvez-Ruiz, M. J.; Molina-Bolívar, J. A.; Holgado-Terriza, J. A.; Cabrerizo-Vílchez, M. Á.; Maldonado-Valderrama, J. Applications of serum albumins in delivery systems: Differences in interfacial behaviour and interacting abilities with polysaccharides. Adv. Colloid Interface Sci. 2021, 290, 102365.

    CAS  Google Scholar 

  51. Wang, Y.; Tong, Q.; Ma, S. R.; Zhao, Z. X.; Pan, L. B.; Cong, L.; Han, P.; Peng, R.; Yu, H.; Lin, Y. et al. Oral berberine improves brain dopa/dopamine levels to ameliorate Parkinson’s disease by regulating gut microbiota. Signal Transduct Target Ther. 2021, 6, 77.

    Google Scholar 

  52. Reinert, A.; Morawski, M.; Seeger, J.; Arendt, T.; Reinert, T. Iron concentrations in neurons and glial cells with estimates on ferritin concentrations. BMC Neurosci. 2019, 20, 25.

    Google Scholar 

  53. Wu, W. C.; Hu, D. N.; Gao, H. X.; Chen, M.; Wang, D. W.; Rosen, R.; McCormick, S. A. Subtoxic levels hydrogen peroxide-induced production of interleukin-6 by retinal pigment epithelial cells. Mol. Vis. 2010, 16, 1864–1873.

    CAS  Google Scholar 

  54. Honarmand Ebrahimi, K.; Bill, E.; Hagedoorn, P. L.; Hagen, W. R. The catalytic center of ferritin regulates iron storage via Fe(II)–Fe(III) displacement. Nat. Chem. Biol. 2012, 8, 941–948.

    CAS  Google Scholar 

  55. Denton, T.; Howard, B. D. A dopaminergic cell line variant resistant to the neurotoxin 1-Methyl-4-Phenyl-1, 2, 3, 6-tetrahydropyridine. J. Neurochem. 1987, 49, 622–630.

    CAS  Google Scholar 

  56. Ochu, E. E.; Rothwell, N. J.; Waters, C. M. Caspases mediate 6-hydroxydopamine-induced apoptosis but not necrosis in PC12 Cells. J. Neurochem. 1998, 70, 2637–2640.

    CAS  Google Scholar 

  57. Evetts, K. D.; Uretsky, N. J.; Iversen, L. L.; Iversen, S. D. Effects of 6-hydroxydopamine on CNS catecholamines, spontaneous motor activity and amphetamine induced hyperactivity in rats. Nature 1970, 225, 961–962.

    CAS  Google Scholar 

  58. Heikkila, R. E.; Cohen, G. 6-Hydroxydopamine: Evidence for superoxide radical as an oxidative intermediate. Science 1973, 181, 456–457.

    CAS  Google Scholar 

  59. Cheng, W.; Zeng, X. W.; Chen, H. Z.; Li, Z. M.; Zeng, W. F.; Mei, L.; Zhao, Y. L. Versatile polydopamine platforms: Synthesis and promising applications for surface modification and advanced nanomedicine. ACS Nano 2019, 13, 8537–8565.

    CAS  Google Scholar 

  60. Di Salvio, M.; Di Giovannantonio, L. G.; Acampora, D.; Prosperi, R.; Omodei, D.; Prakash, N.; Wurst, W.; Simeone, A. Otx2 controls neuron subtype identity in ventral tegmental area and antagonizes vulnerability to MPTP. Nat. Neurosci. 2010, 13, 1481–1488.

    CAS  Google Scholar 

  61. You, L. H.; Wang, J.; Liu, T. Q.; Zhang, Y. L.; Han, X. X.; Wang, T.; Guo, S. S.; Dong, T. Y.; Xu, J. C.; Anderson, G. J. et al. Targeted brain delivery of rabies virus glycoprotein 29-modified deferoxamine-loaded nanoparticles reverses functional deficits in parkinsonian mice. ACS Nano 2018, 12, 4123–4139.

    CAS  Google Scholar 

  62. Wei, Z. Y. D.; Shetty, A. K. Treating Parkinson’s disease by astrocyte reprogramming: Progress and challenges. Sci. Adv. 2021, 7, eabg3198.

    CAS  Google Scholar 

  63. Noble, E. E.; Wang, Z.; Liu, C. M.; Davis, E. A.; Suarez, A. N.; Stein, L. M.; Tsan, L.; Terrill, S. J.; Hsu, T. M.; Jung, A. H. et al. Hypothalamus-hippocampus circuitry regulates impulsivity via melanin-concentrating hormone. Nat. Commun. 2019, 10, 4923.

    Google Scholar 

Download references

Acknowledgements

This work was supported by National Natural Science Foundation of China (Nos. 22175085 and 21875101), National Key Research and Development Program of China (No. 2017YFA0701301), and State Key Laboratory of Analytical Chemistry for Life Science (No. SKLACLS2219).

Author information

Author notes

  1. Ke Yao and Jiamin Gan contributed equally to this work.

Authors and Affiliations

  1. Department of Polymer Science & Engineering and Key Laboratory of High-Performance Polymer Materials and Technology of MOE, School of Chemistry & Chemical Engineering, Nan**g University, Nan**g, 210023, China

    Ke Yao, Jiamin Gan, Di Zhao, Mingding Li, **aoquan Shen, Peijian Feng & Qundong Shen

  2. Key Laboratory for Neuroregeneration of Jiangsu Province and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, 226001, China

    Ke Yao & Yumin Yang

  3. Medical School of Nan**g University, Nan**g, 210008, China

    Qundong Shen

  4. State Key Laboratory of Analytical Chemistry for Life Science, Nan**g University, Nan**g, 210023, China

    Qundong Shen

Authors
  1. Ke Yao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jiamin Gan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Di Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mingding Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. **aoquan Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yumin Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Peijian Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Qundong Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Yumin Yang, Peijian Feng or Qundong Shen.

Electronic Supplementary Material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yao, K., Gan, J., Zhao, D. et al. A core-satellite-like nanoassembly reverses a decisive tyrosine hydroxylase loss in degenerative dopaminergic neurons. Nano Res. 16, 9835–9847 (2023). https://doi.org/10.1007/s12274-023-5729-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12274-023-5729-4

Keywords

Search

Navigation