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 KD 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.