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

• Published in: Nanoscale Vol. 15; no. 45; pp. 18337 - 18346
• Main Authors: Semerdzhiev, Slav A, Segers-Nolten, Ine, van der Schoot, Paul, Blum, Christian, Claessens, Mireille M. A. E
• Format: Journal Article
• Language: English
• Published: Cambridge Royal Society of Chemistry 23.11.2023
• Subjects: Parkinson's disease; Proteins; Severe acute respiratory syndrome coronavirus 2; Transformations; Viral diseases
• ISSN: 2040-3364; 2040-3372
• DOI: 10.1039/d3nr03556e

The presence of deposits of alpha-synuclein (αS) fibrils in the cells of the brain is 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 the disease onset. One of the external factors that may influence the disease onset is viral infection. It has recently been shown in in vitro assays 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 the 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. Mixed amyloid fibrils, composed of two different proteins, have not been observed before. After the depletion of N-protein, fibril formation comes to a halt, until a slow transformation into fibrils with characteristics of a pure αS fibril strain occurs. This transformation into a strain of αS fibrils subsequently results in a second phase of fibril growth until a new equilibrium is reached. We hypothesize that this fibril strain transformation may be of relevance in the cell-to-cell spread of the αS pathology and disease onset. SARS-CoV-2's N-protein accelerates αS aggregation, initially forming a composite αS/N-protein amyloid fibril strain that in time evolves into a strain of αS fibrils which can likely propagate without N-protein, even in uninfected cells.