α-Synuclein Aggregate-Disassembling Compounds Prolong Survival in a Mouse Model of Parkinson's Disease

Abstract

Pathological aggregation of α-synuclein drives neuronal loss in Parkinson's disease. We therefore tested two optimized all-d-peptides, SVD-17 and SVD-1a, alongside the prototype SVD-1. Surface plasmon resonance revealed that SVD-17 binds monomeric α-synuclein with a nanomolar K_D of 1.09 nM. In vitro, SVD-17 and SVD-1a dismantled existing fibrils, rendering 50 % of them seeding-incompetent at 1.4 µM and 5.1 µM, respectively, and suppressed seeded aggregation in HEK293 α-synuclein biosensor cells with an IC₅₀ of 1.6 µM. Hemizygous TgM83^+/− mice received continuous subcutaneous infusion of each peptide for 3 months following intraperitoneal fibril seeding and were then monitored for neurological decline. Treatment with SVD-17 or SVD-1a extended median survival by 14% and 15%, whereas SVD-1 provided no significant benefit. Collectively, SVD-17 and SVD-1a bind α-synuclein with high affinity, disaggregate pathogenic assemblies, block further polymerization, and improve outcomes in a stringent in vivo model, underscoring their potential as disease-modifying therapeutics for Parkinson's disease and other synucleinopathies.