Interactions between SARS-CoV-2 N-Protein and α-Synuclein Accelerate Amyloid Formation

Abstract

First cases that point at a correlation between SARS-CoV-2 infections and the development of Parkinson’s disease (PD) have been reported. Currently, it is unclear if there is also a direct causal link between these diseases. To obtain first insights into a possible molecular relation between viral infections and the aggregation of α-synuclein protein into amyloid fibrils characteristic for PD, we investigated the effect of the presence of SARS-CoV-2 proteins on α-synuclein aggregation. We show, in test tube experiments, that SARS-CoV-2 spike protein (S-protein) has no effect on α-synuclein aggregation, while SARS-CoV-2 nucleocapsid protein (N-protein) considerably speeds up the aggregation process. We observe the formation of multiprotein complexes and eventually amyloid fibrils. Microinjection of N-protein in SH-SY5Y cells disturbed the α-synuclein proteostasis and increased cell death. Our results point toward direct interactions between the N-protein of SARS-CoV-2 and α-synuclein as molecular basis for the observed correlation between SARS-CoV-2 infections and Parkinsonism.

Contribution of Autophagy-Lysosomal Pathway in the Exosomal Secretion of Alpha-Synuclein and Its Impact in the Progression of Parkinson’s Disease

“…Recently, in vitro study reported that proteins from SARS-CoV-2, which causes COVID-19, interact with α-syn, speeding up the formation of amyloid plaques ( Semerdzhiev et al, 2021 ) open an interesting research field associating virus infections with PD or other neurodegenerative diseases development.…”

Parkinson’s Disease in Light of the COVID-19 Pandemic

“…It is suggested that SARS-CoV-2 neuroinfection leads to elevated alpha-synuclein levels [ 6 , 24 ]. Alpha-synuclein is a presynaptic protein expressed among others in the substantia nigra and thalamus and is one of the major constituents of Lewy bodies.…”

“…Experimental studies showed that a persistently elevated level of alpha-synuclein promotes the formation of aggregates that are characteristic for neurodegenerative diseases including PD [ 29 , 31 ]. Semerdzhiev et al identified a SARS-CoV-2 protein that promotes aggregation of the alpha-synuclein in a test tube [ 6 ]. The acceleration of the onset of alpha-synuclein aggregation was observed in the presence of the SARS-CoV-2 nucleocapsid protein (N-protein).…”

“…The acceleration of the onset of alpha-synuclein aggregation was observed in the presence of the SARS-CoV-2 nucleocapsid protein (N-protein). This may suggest the possibility of future development of parkinsonism/PD symptoms in COVID-19 recovery patients [ 6 ].…”

“…Nonetheless, the interplay between SARS-CoV-2 and abundant ACE2 receptors gives solid grounds to discuss the role of COVID-19 in neurodegenerative conditions. Recent studies indicate that there may exist (not yet elucidated) a molecular link between the infection and the pathogenesis of Alzheimer’s disease, multiple sclerosis, and Parkinson’s disease (PD)/parkinsonism [ 1 , 3 , 6 , 7 , 8 , 9 ].…”