The study findings were published on a preprint server and are currently being peer reviewed. https://www.biorxiv.org/content/10.1101/2022.02.21.481360v1
As virus-induced amyloid-formation has been observed in vitro5, and may suggest onset of Parkinson’s Disease and related neurodegenerative diseases 2–5 as potential long-term risk for COVID-19 patients, it is important to investigate how amyloidogenic regions of SARS-COV-2 initiate or accelerate formation of α-synuclein aggregates, the cytotoxic agent in Parkinson’s Disease.6
For this purpose, we have studied, using all-atom molecular dynamics simulations, how interaction with a short segment (SK9) of the
We find that the presence of SK9 changes the ensemble of α-synuclein not only toward more aggregation-prone conformations but that this effect likely leads to a preference for the rod fibril motif. Crucial for this effect is a change in the contact pattern that causes higher flexibility, reduced helix-propensity and larger exposure of residues, especially in the segment E46-A56 that form in the rod fibril polymorph (see Figure 6) the inter-protofilament interface.
Especially important is the increase infrequency and lifetime of the two contacts E46-K80 and V52-A76. Both are found also in the experimentally resolved rod-fibril form, and the mutation E46K, which destroys the salt-bridge E46-K80, is one of the familial mutations that cause Parkinson’s Disease and that shift the equilibrium from rod to twister fibrils.16
The outcome of our fibril simulations is less obvious. While we see some stabilization of the fibril geometries in the presence of SK9, the signal is weak, and it is only for the twister form correlated with a clear change in the contact pattern.
The preference for monomer conformations that likely seed the rod-like fibrils is interesting as the twister fibril is considered to be more cytotoxic.16
It will be especially interesting to compare our work with recent studies into the amyloidogenesis of Spike-protein fragments after endoproteolysis.39