Moderate Binding between Two SARS-CoV-2 Protein Segments and alpha-Synuclein Alters Its Toxic Oligomerization Propensity Differently

The neurological symptoms of long COVID and viral neuroinvasion have raised concerns about the potential interactions between SARS-CoV-2 protein segments and neuronal proteins, which might confer a risk of post-infection neurodegeneration, but the underlying mechanisms remain unclear. Here, we reported that the receptor-binding domain (RBD) of the spike protein and the nine-residue segment (SK9) of the envelope protein could bind to alpha- synuclein (alpha Syn) with Kd values of 503 +/- 24 nM and 12.7 +/- 1.6 mu M, respectively. RBD could inhibit alpha Syn fibrillization by blocking the non-amyloid-beta component region and mediating its antiparallel beta-sheet structural conversions. Omicron-RBD (BA.5) was shown to have a slightly stronger affinity for alpha Syn (Kd = 235 +/- 10 nM), which implies similar effects, whereas SK9 may bind to the C-terminus which accelerates the formation of parallel beta-sheet-containing oligomers and abruptly increases the rate of membrane disruption by 213%. Our results provide plausible molecular insights into the impact of SARS-CoV-2 post-infection and the oligomerization propensity of alpha Syn that is associated with Parkinson's disease.