SARS-CoV-2 Spike Protein 1 Causes Aggregation of α-Synuclein via Microglia-Induced Inflammation and Production of Mitochondrial ROS: Potential Therapeutic Applications of Metformin
Moon Han Chang, Jung Hyun Park, Hye Kyung Lee, Ji Young Choi, Young Ho Koh
Biomedicines, doi:10.3390/biomedicines12061223
Abnormal aggregation of α-synuclein is the hallmark of neurodegenerative diseases, classified as α-synucleinopathies, primarily occurring sporadically. Their onset is associated with an interaction between genetic susceptibility and environmental factors such as neurotoxins, oxidative stress, inflammation, and viral infections. Recently, evidence has suggested an association between neurological complications in long COVID (sometimes referred to as 'post-acute sequelae of COVID-19') and α-synucleinopathies, but its underlying mechanisms are not completely understood. In this study, we first showed that SARS-CoV-2 Spike protein 1 (S1) induces α-synuclein aggregation associated with activation of microglial cells in the rodent model. In vitro, we demonstrated that S1 increases aggregation of α-synuclein in BE(2)M-17 dopaminergic neurons via BV-2 microglia-mediated inflammatory responses. We also identified that S1 directly affects aggregation of α-synuclein in dopaminergic neurons through increasing mitochondrial ROS, though only under conditions of sufficient α-Syn accumulation. In addition, we observed a synergistic effect between S1 and the neurotoxin MPP+ S1 treatment. Combined with a low dose of MPP+, it boosted α-synuclein aggregation and mitochondrial ROS production compared to S1 or the MPP+ treatment group. Furthermore, we evaluated the therapeutic effects of metformin. The treatment of metformin suppressed the S1-induced inflammatory response and α-synucleinopathy. Our findings demonstrate that S1 promotes α-synucleinopathy via both microglia-mediated inflammation and mitochondrial ROS, and they provide pathological insights, as well as a foundation for the clinical management of α-synucleinopathies and the onset of neurological symptoms after the COVID-19 outbreak.
Supplementary Materials: The following supporting information can be downloaded at www.mdpi.com/xxx/s1. Supplementary Figure S1 . (A) Immunoblot analysis using his-tag specific antibody to identify that S1 enter to striatum of rat brain after intranasal administration. (B) Representative images of immunoblot analysis using specific antibody for aggregated α-Syn (5G4), phospho-α-Syn (Ser129), and monomeric α-Syn in 500 ng/mL S1-treated normal BE(2)M-17. (C-E) Quantification of immunoblot analysis for aggregated α-Syn (5G4), phospho-α-Syn (Ser129), and monomeric α-Syn. (F) Representative images of TH staining in the rat substantia nigra and (G) quantification of data. All data are presented as mean ± standard error of the mean (n = 3-5 per group, * p < 0.05). Supplementary Table S1 . Lists of antibodies. Author Contributions: M.H.C.: conceptualization, writing-original draft, methodology, data curation, investigation. J.H.P.: conceptualization, writing-review and editing, methodology, data curation, investigation. H.K.L.: writing-review and editing, methodology, investigation. J.Y.C.: conceptualization, writing-review and editing. Y.H.K.: conceptualization, funding acquisition, review and supervision, writing-review and editing. All authors have read and agreed to the published version of the manuscript.
Institutional Review Board Statement: The animal protocol used was reviewed and approved by the KCDC-Institutional Animal Care and Use Committee (KCDC-IACUC; Approval..
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'abstract': '<jats:p>Abnormal aggregation of α-synuclein is the hallmark of neurodegenerative diseases, '
'classified as α-synucleinopathies, primarily occurring sporadically. Their onset is '
'associated with an interaction between genetic susceptibility and environmental factors such '
'as neurotoxins, oxidative stress, inflammation, and viral infections. Recently, evidence has '
'suggested an association between neurological complications in long COVID (sometimes referred '
'to as ‘post-acute sequelae of COVID-19’) and α-synucleinopathies, but its underlying '
'mechanisms are not completely understood. In this study, we first showed that SARS-CoV-2 '
'Spike protein 1 (S1) induces α-synuclein aggregation associated with activation of microglial '
'cells in the rodent model. In vitro, we demonstrated that S1 increases aggregation of '
'α-synuclein in BE(2)M-17 dopaminergic neurons via BV-2 microglia-mediated inflammatory '
'responses. We also identified that S1 directly affects aggregation of α-synuclein in '
'dopaminergic neurons through increasing mitochondrial ROS, though only under conditions of '
'sufficient α-Syn accumulation. In addition, we observed a synergistic effect between S1 and '
'the neurotoxin MPP+ S1 treatment. Combined with a low dose of MPP+, it boosted α-synuclein '
'aggregation and mitochondrial ROS production compared to S1 or the MPP+ treatment group. '
'Furthermore, we evaluated the therapeutic effects of metformin. The treatment of metformin '
'suppressed the S1-induced inflammatory response and α-synucleinopathy. Our findings '
'demonstrate that S1 promotes α-synucleinopathy via both microglia-mediated inflammation and '
'mitochondrial ROS, and they provide pathological insights, as well as a foundation for the '
'clinical management of α-synucleinopathies and the onset of neurological symptoms after the '
'COVID-19 outbreak.</jats:p>',
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