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SARS-CoV-2 Spike Protein S1 Domain Accelerates α-Synuclein Phosphorylation and Aggregation in Cellular Models of Synucleinopathy

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Abstract

The 2019 novel coronavirus disease (COVID-19) is an infectious disease that began to spread globally since 2019. Some COVID-19 patients have neurological complications, such as olfactory disorders and movement disorders, which coincide with the symptoms of Parkinson’s disease (PD). Increasing imaging and autopsy evidence supports that the density of dopaminergic neurons in the nigrostriatal pathway is damaged in some COVID-19 patients. However, the underlying mechanism that causes PD-like symptoms remains unclear. PD is an age-related neurodegenerative disease with Lewy bodies (LBs) as its histopathologic feature. The main component of LBs is abnormally aggregated α-synuclein (α-syn). The prion-like propagation of α-syn aggregates plays a key role in the onset and progression of PD. The spike protein (S protein) of SARS-CoV-2 is a heparin-binding protein that mediates the entry of the virus into host cells. Here we found that the S1 domain interacts with α-syn and promotes α-syn aggregation. The S1 domain induces mitochondrial dysfunction, oxidative stress, and cytotoxicity. The S1-seeded α-syn fibrils show enhanced seeding activity and induce synaptic damage and cytotoxicity. Thus, the S1 domain of SARS-CoV-2 promotes the aggregation of α-syn in the cellular model of synucleinopathy and may contribute to the pathogenesis of PD.

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Data Availability

The authors declare that all data supporting the findings of this study are available within the article and its supplementary information files. The datasets generated during and analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G et al (2020) Clinical features of patients infected with 2019 novel coronavirus in wuhan, china. Lancet 395(10223):497–506. https://doi.org/10.1016/S0140-6736(20)30183-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Hu B, Guo H, Zhou P, Shi ZL (2021) Characteristics of SARS-cov-2 and covid-19. Nat Rev Microbiol 19(3):141–154. https://doi.org/10.1038/s41579-020-00459-7

    Article  CAS  PubMed  Google Scholar 

  3. Han Q, Lin Q, Jin S, You L (2020) Coronavirus 2019-ncov: a brief perspective from the front line. J Infect 80(4):373–377. https://doi.org/10.1016/j.jinf.2020.02.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. (2020) Note from the editors: world health organization declares novel coronavirus (2019-ncov) sixth public health emergency of international concern. Eurosurveillance 25(5). https://doi.org/10.2807/1560-7917.ES.2020.25.5.200131e

  5. Nalbandian A, Desai AD, Wan EY (2023) Post-covid-19 condition. Annu Rev Med 74:55–64. https://doi.org/10.1146/annurev-med-043021-030635

    Article  CAS  PubMed  Google Scholar 

  6. Nasserie T, Hittle M, Goodman SN (2021) Assessment of the frequency and variety of persistent symptoms among patients with covid-19: a systematic review. Jama Netw Open 4(5):e2111417. https://doi.org/10.1001/jamanetworkopen.2021.11417

    Article  PubMed  PubMed Central  Google Scholar 

  7. Helbok R, Chou SH, Beghi E, Mainali S, Frontera J, Robertson C, Fink E, Schober M et al (2020) Neurocovid: it’s time to join forces globally. Lancet Neurol 19(10):805–806. https://doi.org/10.1016/S1474-4422(20)30322-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Dulski J, Slawek J (2023) Incidence and characteristics of post-covid-19 parkinsonism and dyskinesia related to covid-19 vaccines. Neurol Neurochir Pol 57(1):53–62. https://doi.org/10.5603/PJNNS.a2023.0011

    Article  PubMed  Google Scholar 

  9. Leta V, Boura I, van Wamelen DJ, Rodriguez-Violante M, Antonini A, Chaudhuri KR (2022) Covid-19 and parkinson’s disease: acute clinical implications, long-covid and post-covid-19 parkinsonism. Int Rev Neurobiol 165:63–89. https://doi.org/10.1016/bs.irn.2022.04.004

    Article  PubMed  PubMed Central  Google Scholar 

  10. Brown EG, Chahine LM, Goldman SM, Korell M, Mann E, Kinel DR, Arnedo V, Marek KL et al (2020) The effect of the covid-19 pandemic on people with parkinson’s disease. J Parkinsons Dis 10(4):1365–1377. https://doi.org/10.3233/JPD-202249

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Huang P, Zhang L, Tan Y, Chen S (2023) Links between covid-19 and parkinson’s disease/alzheimer’s disease: reciprocal impacts, medical care strategies and underlying mechanisms. Transl Neurodegener 12(1). https://doi.org/10.1186/s40035-023-00337-1.

  12. Morassi M, Palmerini F, Nici S, Magni E, Savelli G, Guerra UP, Chieregato M, Morbelli S et al (2021) SARS-cov-2-related encephalitis with prominent parkinsonism: clinical and fdg-pet correlates in two patients. J Neurol 268(11):3980–3987. https://doi.org/10.1007/s00415-021-10560-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Douaud G, Lee S, Alfaro-Almagro F, Arthofer C, Wang C, Mccarthy P, Lange F, Andersson JLR et al (2022) SARS-cov-2 is associated with changes in brain structure in uk biobank. Nature 604(7907):697–707. https://doi.org/10.1038/s41586-022-04569-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Xu E, Xie Y, Al-Aly Z (2022) Long-term neurologic outcomes of covid-19. Nat Med 28(11):2406–2415. https://doi.org/10.1038/s41591-022-02001-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Song E, Zhang C, Israelow B, Lu-Culligan A, Prado AV, Skriabine S, Lu P, Weizman O et al (2021) Neuroinvasion of SARS-cov-2 in human and mouse brain. J Exp Med 218(3). https://doi.org/10.1084/jem.20202135

  16. Meinhardt J, Radke J, Dittmayer C, Franz J, Thomas C, Mothes R, Laue M, Schneider J et al (2021) Olfactory transmucosal SARS-cov-2 invasion as a port of central nervous system entry in individuals with covid-19. Nat Neurosci 24(2):168–175. https://doi.org/10.1038/s41593-020-00758-5

    Article  CAS  PubMed  Google Scholar 

  17. Cama VF, Marin-Prida J, Acosta-Rivero N, Acosta EF, Diaz LO, Casadesus AV, Fernandez-Marrero B, Gilva-Rodriguez N et al (2021) The microglial nlrp3 inflammasome is involved in human SARS-cov-2 cerebral pathogenicity: a report of three post-mortem cases. J Neuroimmunol 361:577728. https://doi.org/10.1016/j.jneuroim.2021.577728

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Xu J, Lazartigues E (2022) Expression of ace2 in human neurons supports the neuro-invasive potential of covid-19 virus. Cell Mol Neurobiol 42(1):305–309. https://doi.org/10.1007/s10571-020-00915-1

    Article  CAS  PubMed  Google Scholar 

  19. Ding C, Wu Y, Chen X, Chen Y, Wu Z, Lin Z, Kang D, Fang W et al (2022) Global, regional, and national burden and attributable risk factors of neurological disorders: the global burden of disease study 1990–2019. Front Public Health 10:952161. https://doi.org/10.3389/fpubh.2022.952161

    Article  PubMed  PubMed Central  Google Scholar 

  20. Armstrong MJ, Okun MS (2020) Diagnosis and treatment of parkinson disease: a review. JAMA 323(6):548–560. https://doi.org/10.1001/jama.2019.22360

    Article  PubMed  Google Scholar 

  21. Tolosa E, Garrido A, Scholz SW, Poewe W (2021) Challenges in the diagnosis of parkinson’s disease. Lancet Neurol 20(5):385–397. https://doi.org/10.1016/S1474-4422(21)00030-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Rocha EM, De Miranda B, Sanders LH (2018) Alpha-synuclein: pathology, mitochondrial dysfunction and neuroinflammation in parkinson’s disease. Neurobiol Dis 109(Pt B):249–257. https://doi.org/10.1016/j.nbd.2017.04.004

    Article  CAS  PubMed  Google Scholar 

  23. Blauwendraat C, Nalls MA, Singleton AB (2020) The genetic architecture of parkinson’s disease. Lancet Neurol 19(2):170–178. https://doi.org/10.1016/S1474-4422(19)30287-X

    Article  CAS  PubMed  Google Scholar 

  24. Burre J, Sharma M, Sudhof TC (2018) Cell biology and pathophysiology of alpha-synuclein. Cold Spring Harb Perspect Med 8(3). https://doi.org/10.1101/cshperspect.a024091

  25. Tofaris GK (2022) Initiation and progression of alpha-synuclein pathology in parkinson’s disease. Cell Mol Life Sci 79(4):210. https://doi.org/10.1007/s00018-022-04240-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Du XY, Xie XX, Liu RT (2020) The role of alpha-synuclein oligomers in parkinson’s disease. Int J Mol Sci 21(22). https://doi.org/10.3390/ijms21228645

  27. Dai L, Wang J, He M, Xiong M, Tian Y, Liu C, Zhang Z (2021) Lovastatin alleviates α-synuclein aggregation and phosphorylation in cellular models of synucleinopathy. Front Molec Neurosci 14. https://doi.org/10.3389/fnmol.2021.682320

  28. Vaquer-Alicea J, Diamond MI (2019) Propagation of protein aggregation in neurodegenerative diseases. Annu Rev Biochem 88:785–810. https://doi.org/10.1146/annurev-biochem-061516-045049

    Article  CAS  PubMed  Google Scholar 

  29. Tanudjojo B, Shaikh SS, Fenyi A, Bousset L, Agarwal D, Marsh J, Zois C, Heman-Ackah S et al (2021) Phenotypic manifestation of alpha-synuclein strains derived from parkinson’s disease and multiple system atrophy in human dopaminergic neurons. Nat Commun 12(1):3817. https://doi.org/10.1038/s41467-021-23682-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Koga S, Sekiya H, Kondru N, Ross OA, Dickson DW (2021) Neuropathology and molecular diagnosis of synucleinopathies. Mol Neurodegener 16(1):83. https://doi.org/10.1186/s13024-021-00501-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Bloem BR, Okun MS, Klein C (2021) Parkinson’s disease. Lancet 397(10291):2284–2303. https://doi.org/10.1016/S0140-6736(21)00218-X

    Article  CAS  PubMed  Google Scholar 

  32. Lau A, So R, Lau H, Sang JC, Ruiz-Riquelme A, Fleck SC, Stuart E, Menon S et al (2020) Alpha-synuclein strains target distinct brain regions and cell types. Nat Neurosci 23(1):21–31. https://doi.org/10.1038/s41593-019-0541-x

    Article  CAS  PubMed  Google Scholar 

  33. Tian Y, Meng L, Zhang Z (2020) What is strain in neurodegenerative diseases? Cell Mol Life Sci 77(4):665–676. https://doi.org/10.1007/s00018-019-03298-9

    Article  CAS  PubMed  Google Scholar 

  34. V’Kovski P, Kratzel A, Steiner S, Stalder H, Thiel V (2021) Coronavirus biology and replication: implications for SARS-cov-2. Nat Rev Microbiol 19(3):155–170. https://doi.org/10.1038/s41579-020-00468-6

    Article  CAS  PubMed  Google Scholar 

  35. Wong NA, Saier MJ (2021) The SARS-coronavirus infection cycle: a survey of viral membrane proteins, their functional interactions and pathogenesis. Int J Mol Sci 22(3). https://doi.org/10.3390/ijms22031308

  36. Jackson CB, Farzan M, Chen B, Choe H (2022) Mechanisms of SARS-cov-2 entry into cells. Nat Rev Mol Cell Biol 23(1):3–20. https://doi.org/10.1038/s41580-021-00418-x

    Article  CAS  PubMed  Google Scholar 

  37. Bar-On YM, Flamholz A, Phillips R, Milo R (2020) SARS-cov-2 (covid-19) by the numbers. Elife 9. https://doi.org/10.7554/eLife.57309

  38. Frolova EI, Palchevska O, Lukash T, Dominguez F, Britt W, Frolov I (2022) Acquisition of furin cleavage site and further SARS-cov-2 evolution change the mechanisms of viral entry, infection spread, and cell signaling. J Virol 96(15). https://doi.org/10.1128/jvi.00753-22

  39. Tavassoly O, Safavi F, Tavassoly I (2020) Heparin-binding peptides as novel therapies to stop SARS-cov-2 cellular entry and infection. Mol Pharmacol 98(5):612–619. https://doi.org/10.1124/molpharm.120.000098

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Mycroft-West CJ, Su D, Elli S, Li Y, Guimond SE, Miller GJ, Turnbull JE, Yates EA et al (2020) The 2019 coronavirus (SARS-cov-2) surface protein (spike) s1 receptor binding domain undergoes conformational change upon heparin binding. Cold Spring Harbor Laboratory Press, Cold Spring Harbor. https://doi.org/10.1101/2020.02.29.971093

  41. Tavassoly O, Safavi F, Tavassoly I (2020) Seeding brain protein aggregation by SARS-cov-2 as a possible long-term complication of covid-19 infection. Acs Chem Neurosci 11(22):3704–3706. https://doi.org/10.1021/acschemneuro.0c00676

    Article  CAS  PubMed  Google Scholar 

  42. Petrlova J, Samsudin F, Bond PJ, Schmidtchen A (2022) SARS-cov-2 spike protein aggregation is triggered by bacterial lipopolysaccharide. Febs Lett 596(19):2566–2575. https://doi.org/10.1002/1873-3468.14490

    Article  CAS  PubMed  Google Scholar 

  43. Idrees D, Kumar V (2021) SARS-cov-2 spike protein interactions with amyloidogenic proteins: potential clues to neurodegeneration. Biochem Biophys Res Commun 554:94–98. https://doi.org/10.1016/j.bbrc.2021.03.100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Wu Z, Zhang X, Huang Z, Ma K (2022) SARS-cov-2 proteins interact with alpha synuclein and induce lewy body-like pathology in vitro. Int J Mol Sci 23(6):3394. https://doi.org/10.3390/ijms23063394

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Nyström S, Hammarström P (2022) Amyloidogenesis of SARS-cov-2 spike protein. J Am Chem Soc 144(20):8945–8950. https://doi.org/10.1021/jacs.2c03925

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Volpicelli-Daley LA, Luk KC, Lee VM (2014) 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(9):2135–2146. https://doi.org/10.1038/nprot.2014.143

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Hilgenberg LG, Smith MA (2007) Preparation of dissociated mouse cortical neuron cultures. J Vis Exp (10):562. https://doi.org/10.3791/562

  48. Ryan BJ, Hoek S, Fon EA, Wade-Martins R (2015) Mitochondrial dysfunction and mitophagy in parkinson’s: from familial to sporadic disease. Trends Biochem Sci 40(4):200–210. https://doi.org/10.1016/j.tibs.2015.02.003

    Article  CAS  PubMed  Google Scholar 

  49. Han S, Zhang M, Jeong YY, Margolis DJ, Cai Q (2021) The role of mitophagy in the regulation of mitochondrial energetic status in neurons. Autophagy 17(12):4182–4201. https://doi.org/10.1080/15548627.2021.1907167

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Solomon IH, Normandin E, Bhattacharyya S, Mukerji SS, Keller K, Ali AS, Adams G, Hornick JL et al (2020) Neuropathological features of covid-19. N Engl J Med 383(10):989–992. https://doi.org/10.1056/NEJMc2019373

    Article  PubMed  Google Scholar 

  51. Matschke J, Lutgehetmann M, Hagel C, Sperhake JP, Schroder AS, Edler C, Mushumba H, Fitzek A et al (2020) Neuropathology of patients with covid-19 in germany: a post-mortem case series. Lancet Neurol 19(11):919–929. https://doi.org/10.1016/S1474-4422(20)30308-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Stroylova Y, Konstantinova A, Stroylov V, Katrukha I, Rozov F, Muronetz V (2023) Does the SARS-cov-2 spike receptor-binding domain hamper the amyloid transformation of alpha-synuclein after all? Biomedicines 11(2):498. https://doi.org/10.3390/biomedicines11020498

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Semerdzhiev SA, Fakhree MAA, Segers-Nolten I, Blum C, Claessens MMAE (2022) Interactions between SARS-cov-2 n-protein and α-synuclein accelerate amyloid formation. Acs Chem Neurosci 13(1):143–150. https://doi.org/10.1021/acschemneuro.1c00666

    Article  CAS  PubMed  Google Scholar 

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Funding

This work was supported by grants from the National Natural Science Foundation of China (No. 82271447 and 81901090), the National Key Research and Development Program of China (2019YFE0115900), the Innovative Research Groups of Hubei Province (2022CFA026), and the “New 20 Terms of Universities in Jinan” grant (No. 202228022).

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  1. Jiannan Wang and Lijun Dai contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, 430060, China

    Jiannan Wang, Lijun Dai, Min Deng, Tingting Xiao, Zhaohui Zhang & Zhentao Zhang

  2. TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430000, China

    Zhentao Zhang

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Zhentao Zhang conceived the project and designed the experiments. Jiannan Wang and Lijun Dai performed most of the experiments and wrote the original draft. Min Deng, Tingting Xiao, and Zhaohui Zhang helped in the data analysis. All authors contributed to the article and approved the submitted version.

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Wang, J., Dai, L., Deng, M. et al. SARS-CoV-2 Spike Protein S1 Domain Accelerates α-Synuclein Phosphorylation and Aggregation in Cellular Models of Synucleinopathy. Mol Neurobiol 61, 2446–2458 (2024). https://doi.org/10.1007/s12035-023-03726-9

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