Hydrophobic residues in the α-synuclein NAC domain drive seed-competent fibril formation and are targeted by peptide inhibitors.

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Alpha-synuclein (αSyn) is a 14-kDa intrinsically disordered protein that aggregates into insoluble fibrils in synucleinopathies, including Lewy bodies, multiple system atrophy, and Parkinson's disease, contributing to neurotoxicity and disease progression. The ability of these fibrils to seed further aggregation of native protein is central to αSyn pathology. Here, we examined the broader non-amyloid component (NAC) domain, focusing on how residues flanking the hydrophobic 68-71 (GAVV) motif of αSyn (residues 8-11 in NAC35) modulate nucleation, stability, and pathological seeding. Using full-length NAC peptide and truncated variants, we show that the 68-71 (GAVV) stretch is critical for nucleation and aggregation into prion-like fibrils. Peptide inhibitors targeting this hydrophobic region block the formation of seed-competent fibrils. Molecular dynamics simulations showed that these inhibitors alter peptide-peptide interactions and contact key hydrophobic residues within the NAC domain. Further analysis indicates that residues beyond the 68-71 (GAVV) motif, such as 79-95, are critical for stabilizing fibrils and promoting seeding competency. Peptide B interactions with key hydrophobic motifs within the NAC domain were visualized in silico, offering mechanistic insights into how it disrupts aggregation.

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