Studies on topological maturation of α-synuclein fibrils in Parkinson's disease: Insights from persistent homology and SARS-CoV-2 acceleration of aggregation.

Background: Parkinson's disease (PD) is marked by the progressive loss of dopaminergic neurons in the substantia nigra and the accumulation of α-synuclein (α-syn) into amyloid fibrils and Lewy bodies. These aggregates impair synaptic function, disrupt proteostasis, compromise mitochondrial health, and drive neuroinflammation and oxidative stress. Clinical observations during the COVID-19 pandemic revealed accelerated motor deterioration and higher mortality among PD patients following SARS-CoV-2 infection, pointing to potential overlapping mechanisms with Alzheimer's disease, including protein misfolding, chronic inflammation, and oxidative damage. Objective: This study aims to investigate how the SARS-CoV-2 N-protein may accelerate α-syn aggregation using computational approaches. Methods: We employed a multimodal, label-free computational pipeline inspired by TopoBind to examine the topological maturation of patient-derived α-syn fibrils across preclinical (PDB 7V47, 8H03), mid-stage (7XO0, 7XO1), and late-stage (8H04, 7V48) PD phases. Per-residue features were extracted using 640-dimensional evolutionary scale modeling (ESM)-2 embeddings, solvent-accessible surface area, and persistent homology based on Vietoris-Rips filtration of Cα coordinates (r = 0-20 Å, persistence threshold > 0.8 Å). Predictions were validated using PyRosetta InterfaceAnalyzerMover, PRODIGY (ΔG and Kd), and normal mode analysis. Results: The pipeline successfully identified key protein-protein interface residues on α-syn fibrils, achieving 74-92% overlap with PyRosetta results. Conserved interaction hotspots were located primarily in the non-amyloid component region, protofilament interfaces, and hydrophobic grooves. Conclusions: Our findings demonstrate that fibril maturation involves progressive expansion of binding interfaces, offering a plausible topological mechanism by which SARS-CoV-2 N-protein can promote pathogenic α-syn conformers and contribute to long-term neurological complications following infection.