ABSTRACT
Aggregates of α-synuclein are thought to be the disease-causing agent in Parkinson's disease. Various case studies have hinted at a correlation between COVID-19 and the onset of Parkinson's disease. For this reason, we use molecular dynamics simulations to study whether amyloidogenic regions in SARS-COV-2 proteins can initiate and modulate aggregation of α-synuclein. As an example, we choose the nine-residue fragment SFYVYSRVK (SK9), located on the C-terminal of the envelope protein of SARS-COV-2. We probe how the presence of SK9 affects the conformational ensemble of α-synuclein monomers and the stability of two resolved fibril polymorphs. We find that the viral protein fragment SK9 may alter α-synuclein amyloid formation by shifting the ensemble toward aggregation-prone and preferentially rod-like fibril seeding conformations. However, SK9 has only a small effect on the stability of pre-existing or newly formed fibrils. A potential mechanism and key residues for potential virus-induced amyloid formation are described.
Subject(s)
Amyloidogenic Proteins , Coronavirus Envelope Proteins , Parkinson Disease , Peptide Fragments , alpha-Synuclein , Amyloidogenic Proteins/chemistry , Amyloidogenic Proteins/metabolism , COVID-19/virology , Coronavirus Envelope Proteins/chemistry , Coronavirus Envelope Proteins/metabolism , Humans , Parkinson Disease/metabolism , Peptide Fragments/chemistry , Peptide Fragments/metabolism , SARS-CoV-2/metabolism , alpha-Synuclein/chemistry , alpha-Synuclein/metabolismABSTRACT
Given the emergence of the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), which particularly threatens older people with comorbidities such as diabetes mellitus and dementia, understanding the relationship between Covid-19 and other diseases is an important factor for treatment. Possible targets for medical intervention include G-quadruplexes (G4Qs) and their protein interaction partners. We investigated the stability and conformational space of the RG-1 RNA-G-quadruplex of the SARS-CoV-2 N-gene in the presence of salts, cosolutes, crowders and intrinsically disordered peptides, focusing on α-Synuclein and the human islet amyloid polypeptide, which are involved in Parkinson's disease (PD) and type-II diabetes mellitus (T2DM), respectively. We found that the conformational dynamics of the RG-1 G4Q is strongly affected by the various solution conditions. Further, the amyloidogenic peptides were found to strongly modulate the conformational equilibrium of the RG-1. Considerable changes are observed with respect to their interaction with human telomeric G4Qs, which adopt different topologies. These results may therefore shed more light on the relationship between PD as well as T2DM and the SARS-CoV-2 disease and their molecular underpinnings. Since dysregulation of G4Q formation by rationally designed targeting compounds affects the control of cellular processes, this study should contribute to the development of specific ligands for intervention.