doi:10.1126/scitranslmed.adu1050engDohoney, Ryan A.Palanikumar, L.Oldani, EmilyBaysah, Charles ZuwuJoseph, Johnson A.Polanco, DavidSantos-Otte, PaulaStillman, Nicholas H.Corcoran, PeterBall, Tyler D.Fitch, Tessa C.Ahmed, JemilOgbonna-Ukuku, IfunayachiReynolds Caicedo, Kevin M.Liu, YingLeehey, Maureen A.Linseman, Daniel A.Paredes, Daniel A.Birol, MelissaCremades, NuniloMagzoub, MazinKumar, SunilFoldamers rescue synucleinopathy phenotypes in multiple in vitro and in vivo modelsART-2026-148875Synucleinopathies is an umbrella term for multiple neurological disorders, including Parkinson’s disease (PD), Lewy body dementia (LBD), and multiple system atrophy (MSA). A central pathological hallmark of synucleinopathies is the aggregation of α-synuclein (αS, a neuronal protein) and its prion-like spread. Therefore, inhibition of αS aggregation and spread is considered a viable therapeutic approach for the treatment of synucleinopathies. Foldamers are synthetic ligands that mimic the secondary structure of proteins. Using an oligoquinoline (OQ) scaffold–based foldamer approach, we have previously identified a foldamer (SK-129) that potently inhibits αS aggregation. Here, using a wide range of biophysical, cellular, and in vivo methods, we showed that SK-129 rescued synucleinopathy phenotypes in cellular, Caenorhabditis elegans, and human induced pluripotent stem cell (iPSC)– derived neuron models. SK-129 specifically bound to neurotoxic αS oligomers with ~6-fold higher affinity (Kd = 221 ± 29 nM) than to physiological αS monomer, validating αS oligomers as a therapeutic target. Furthermore, SK-129 efficiently crossed the blood-brain barrier (BBB) and exhibited favorable pharmaceutical properties in mice. Treatment with SK-129 prevented brain histopathology and increased survival in a mouse model expressing human A53T mutant αS without showing any apparent cytotoxicity. SK-129 inhibited αS aggregation mediated by exosomes derived from C. elegans or patients with PD in HEK293T reporter cells. SK-129 completely inhibited the coaggregation of αS-tau, a pathological biomarker for LBD in both cellular and mouse models. Overall, we report a potent foldamer with therapeutic potential for PD and LBD.2026http://zaguan.unizar.es/record/17040910.1126/scitranslmed.adu1050http://zaguan.unizar.es/record/170409oai:zaguan.unizar.es:170409info:eu-repo/grantAgreement/ES/AEI/PID2022-136997NB-I00SCIENCE TRANSLATIONAL MEDICINE 18, 843 (2026), [17 pp.]by-ndhttps://creativecommons.org/licenses/by-nd/4.0/deed.esinfo:eu-repo/semantics/openAccess