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

Authors

Pranathi Jalapally, Lakshmi Sowmya Emani, Sminu Izudheen, K S Jagannatha Rao

Published in

Journal of Alzheimer's disease reports. Volume 10. Pages 25424823261464972. Epub Jun 26, 2026.

Abstract

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.
This study aims to investigate how the SARS-CoV-2 N-protein may accelerate α-syn aggregation using computational approaches.
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.
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.
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.

PMID:
42876850
Bibliographic data and abstract were imported from PubMed on 15 Oct 2026.

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