SARS-CoV-2 N-protein induces the formation of composite α-synuclein/N-protein fibrils that transform into a strain of α-synuclein fibrils (preprint)

The presence of deposits of alpha-synuclein fibrils in cells of the brain are a hallmark of several -synucleinopathies, including Parkinson's disease. As most disease cases are not familial, it is likely that external factors play a role in disease onset. One of the external factors that may influence disease onset are viral infections. It has recently been shown that in the presence of SARS-Cov-2 N-protein, S fibril formation is faster and proceeds in an unusual two-step aggregation process. Here, we show that faster fibril formation is not due to a SARS-CoV-2 N-protein-catalysed formation of an aggregation-prone nucleus. Instead, aggregation starts with the formation of a population of mixed S/N-protein fibrils with low affinity for S. After the depletion of N-protein, fibril formation comes to a halt, until a slow transformation to fibrils with characteristics of pure S fibril strains occurs. This transformation into a strain of S fibrils subsequently results in a second phase of fibril growth until a new equilibrium is reached. Our findings point at the possible relevance of fibril strain transformation in the cell-to-cell spread of the S pathology and disease onset.

Interactions between SARS-CoV-2 N-protein and α-synuclein accelerate amyloid formation (preprint)

First cases that point at a correlation between SARS-CoV-2 infections and the development of Parkinson's disease have been reported. Currently it is unclear if there also is a direct causal link between these diseases. To obtain first insights into a possible molecular relation between viral infections and the aggregation of -synuclein protein into amyloid fibrils characteristic for Parkinson's disease, we investigated the effect of the presence of SARS-CoV-2 proteins on synuclein aggregation. We show, in test tube experiments, that SARS-CoV-2 S-protein has no effect on -synuclein aggregation while SARS-CoV-2 N-protein considerably speeds up the aggregation process. We observe the formation of multi-protein complexes, and eventually amyloid fibrils. Microinjection of N-protein in SHSY-5Y cells disturbed the -synuclein proteostasis and increased cell death. Our results point toward direct interactions between the N-protein of SARS-CoV-2 and -synuclein as molecular basis for the observed coincidence between SARS-CoV-2 infections and Parkinsonism.