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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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The couple of netrin-1/α-Synuclein regulates the survival of dopaminergic neurons via α-Synuclein disaggregation

  • Eun Ji Kang (Department of Physiology, College of Medicine, Hallym University) ;
  • Seung Min Jang (Department of Physiology, College of Medicine, Hallym University) ;
  • Ye Ji Lee (Department of Physiology, College of Medicine, Hallym University) ;
  • Ye Ji Jeong (Department of Physiology, College of Medicine, Hallym University) ;
  • You Jin Kim (Department of Physiology, College of Medicine, Hallym University) ;
  • Seong Su Kang (Department of Pathology and Laboratory Medicine, Emory University School of Medicine) ;
  • Eun Hee Ahn (Department of Physiology, College of Medicine, Hallym University)
  • Received : 2023.01.12
  • Accepted : 2023.02.04
  • Published : 2023.02.28
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Abstract

The abnormal accumulation and aggregation of the misfolded α-synuclein protein is the neuropathological hallmark of all α-synucleinopathies, including Parkinson's disease. The secreted proteins known as netrins (netrin-1, netrin-3, and netrin-4) are related to laminin and have a role in the molecular pathway for axon guidance and cell survival. Interestingly, only netrin-1 is significantly expressed in the substantia nigra (SN) of healthy adult brains and its expression inversely correlates with that of α-synuclein, which prompted us to look into the role of α-synuclein and netrin-1 molecular interaction in the future of dopaminergic neurons. Here, we showed that netrin-1 and α-synuclein directly interacted in pre-formed fibrils (PFFs) generation test, real time binding assay, and co-immunoprecipitation with neurotoxin treated cell lysates. Netrin-1 deficiency appeared to activate the dopaminergic neuronal cell death signal pathway via α-synuclein aggregation and hyperphosphorylation of α-synuclein S129. Taken together, netrin-1 can be a promising therapeutic molecule in Parkinson's disease.

Keywords

Acknowledgement

This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. 2022R1C1C1006166) and Hallym University Research Fund, 2021 (HRF-202103-009) to E. H. A. We thank S.S.K. for excellent technical assistance for animal model.

References

  1. Serafini T, Kennedy TE, Galko MJ, Mirzayan C, Jessell TM and Tessier-Lavigne M (1994) The netrins define a family of axon outgrowth-promoting proteins homologous to C. elegans UNC-6. Cell 78, 409-424 https://doi.org/10.1016/0092-8674(94)90420-0
  2. Serafini T, Colamarino SA, Leonardo ED et al (1996) Netrin-1 is required for commissural axon guidance in the developing vertebrate nervous system. Cell 87, 1001-1014 https://doi.org/10.1016/S0092-8674(00)81795-X
  3. Lauderdale JD, Davis NM and Kuwada JY (1997) Axon tracts correlate with netrin-1a expression in the zebrafish embryo. Mol Cell Neurosci 9, 293-313 https://doi.org/10.1006/mcne.1997.0624
  4. Tang X, Jang SW, Okada M et al (2008) Netrin-1 mediates neuronal survival through PIKE-L interaction with the dependence receptor UNC5B. Nat Cell Biol 10, 698-706 https://doi.org/10.1038/ncb1732
  5. Rajasekharan S and Kennedy TE (2009) The netrin protein family. Genome Biol 10, 239
  6. Yamagishi S, Yamada K, Sawada M et al (2015) Netrin-5 is highly expressed in neurogenic regions of the adult brain. Front Cell Neurosci 9, 146
  7. Ahn EH, Kang SS, Liu X et al (2021) BDNF and Netrin-1 repression by C/EBPbeta in the gut triggers Parkinson's disease pathologies, associated with constipation and motor dysfunctions. Prog Neurobiol 198, 101905
  8. Jasmin M, Ahn EH, Voutilainen MH et al (2021) Netrin-1 and its receptor DCC modulate survival and death of dopamine neurons and Parkinson's disease features. EMBO J 40, e105537
  9. Blesa J and Przedborski S (2014) Parkinson's disease: animal models and dopaminergic cell vulnerability. Front Neuroanat 8, 155
  10. Olanow CW and Brundin P (2013) Parkinson's disease and alpha synuclein: is Parkinson's disease a prion-like disorder? Mov Disord 28, 31-40 https://doi.org/10.1002/mds.25373
  11. Armstrong MJ and Okun MS (2020) Diagnosis and treatment of Parkinson disease: a review. JAMA 323, 548-560 https://doi.org/10.1001/jama.2019.22360
  12. Kang SS, Ahn EH, Zhang Z et al (2018) Alpha-Synuclein stimulation of monoamine oxidase-B and legumain protease mediates the pathology of Parkinson's disease. EMBO J 37, e98878
  13. Li W, Lesuisse C, Xu Y, Troncoso JC, Price DL and Lee MK (2004) Stabilization of alpha-synuclein protein with aging and familial parkinson's disease-linked A53T mutation. J Neurosci 24, 7400-7409 https://doi.org/10.1523/JNEUROSCI.1370-04.2004
  14. Yoo H, Lee J, Kim B et al (2022) Role of post-translational modifications on the alpha-synuclein aggregation-related pathogenesis of Parkinson's disease. BMB Rep 55, 323-335 https://doi.org/10.5483/BMBRep.2022.55.7.073
  15. Anderson JP, Walker DE, Goldstein JM et al (2006) Phosphorylation of Ser-129 is the dominant pathological modification of alpha-synuclein in familial and sporadic Lewy body disease. J Biol Chem 281, 29739-29752 https://doi.org/10.1074/jbc.M600933200
  16. Paradisi A, Maisse C, Coissieux MM et al (2009) Netrin-1 up-regulation in inflammatory bowel diseases is required for colorectal cancer progression. Proc Natl Acad Sci U S A 106, 17146-17151 https://doi.org/10.1073/pnas.0901767106
  17. Bathina S and Das UN (2015) Brain-derived neurotrophic factor and its clinical implications. Arch Med Sci 11, 1164-1178 https://doi.org/10.5114/aoms.2015.56342
  18. Howells DW, Porritt MJ, Wong JY et al (2000) Reduced BDNF mRNA expression in the Parkinson's disease substantia nigra. Exp Neurol 166, 127-135 https://doi.org/10.1006/exnr.2000.7483
  19. Loeliger MM, Briscoe T and Rees SM (2008) BDNF increases survival of retinal dopaminergic neurons after prenatal compromise. Invest Ophthalmol Vis Sci 49, 1282-1289 https://doi.org/10.1167/iovs.07-0521
  20. Zhang Z, Song M, Liu X et al (2014) Cleavage of tau by asparagine endopeptidase mediates the neurofibrillary pathology in Alzheimer's disease. Nat Med 20, 1254-1262 https://doi.org/10.1038/nm.3700
  21. Zhang Z, Kang SS, Liu X et al (2017) Asparagine endopeptidase cleaves α-synuclein and mediates pathologic activities in Parkinson's disease. Nat Struct Mol Biol 24, 632-642 https://doi.org/10.1038/nsmb.3433
  22. Ahn EH, Kang SS, Liu X et al (2020) Initiation of Parkinson's disease from gut to brain by δ-secretase. Cell Res 30, 70-87 https://doi.org/10.1038/s41422-019-0241-9
  23. Papapetropoulos S and Singer C (2006) Psychiatric comorbidity in a population of Parkinson's disease patients. Eur J Neurol 13, e1
  24. Wang X, Cimermancic P, Yu C et al (2017) Molecular details underlying dynamic structures and regulation of the human 26s proteasome. Mol Cell Proteomics 16, 840-854 https://doi.org/10.1074/mcp.M116.065326
  25. McFarland MA, Ellis CE, Markey SP and Nussbaum RL (2008) Proteomics analysis identifies phosphorylation-dependent alpha-synuclein protein interactions. Mol Cell Proteomics 7, 2123-2137 https://doi.org/10.1074/mcp.M800116-MCP200
  26. Kozakov D, Hall DR, Xia B et al (2017) The ClusPro web server for protein-protein docking. Nat Protoc 12, 255-278 https://doi.org/10.1038/nprot.2016.169
  27. Desta IT, Porter KA, Xia B, Kozakov D and Vajda S (2020) Performance and its limits in rigid body protein-protein docking. Structure 28, 1071-1081 e1073