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

Abstract

AbstractThe presence of deposits of alpha-synuclein fibrils in cells of the brain are a hallmark of several α-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, αS 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 αS/N-protein fibrils with low affinity for αS. After the depletion of N-protein, fibril formation comes to a halt, until a slow transformation to fibrils with characteristics of pure αS fibril strains occurs. This transformation into a strain of αS 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 αS pathology and disease onset.