000170409 001__ 170409
000170409 005__ 20260420103355.0
000170409 0247_ $$2doi$$a10.1126/scitranslmed.adu1050
000170409 0248_ $$2sideral$$a148875
000170409 037__ $$aART-2026-148875
000170409 041__ $$aeng
000170409 100__ $$aDohoney, Ryan A.
000170409 245__ $$aFoldamers rescue synucleinopathy phenotypes in multiple in vitro and in vivo models
000170409 260__ $$c2026
000170409 5060_ $$aAccess copy available to the general public$$fUnrestricted
000170409 5203_ $$aSynucleinopathies 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.
000170409 536__ $$9info:eu-repo/grantAgreement/ES/AEI/PID2022-136997NB-I00
000170409 540__ $$9info:eu-repo/semantics/openAccess$$aby-nd$$uhttps://creativecommons.org/licenses/by-nd/4.0/deed.es
000170409 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000170409 700__ $$aPalanikumar, L.
000170409 700__ $$aOldani, Emily
000170409 700__ $$aBaysah, Charles Zuwu
000170409 700__ $$aJoseph, Johnson A.
000170409 700__ $$0(orcid)0000-0002-0005-6712$$aPolanco, David$$uUniversidad de Zaragoza
000170409 700__ $$aSantos-Otte, Paula
000170409 700__ $$aStillman, Nicholas H.
000170409 700__ $$aCorcoran, Peter
000170409 700__ $$aBall, Tyler D.
000170409 700__ $$aFitch, Tessa C.
000170409 700__ $$aAhmed, Jemil
000170409 700__ $$aOgbonna-Ukuku, Ifunayachi
000170409 700__ $$aReynolds Caicedo, Kevin M.
000170409 700__ $$aLiu, Ying
000170409 700__ $$aLeehey, Maureen A.
000170409 700__ $$aLinseman, Daniel A.
000170409 700__ $$aParedes, Daniel A.
000170409 700__ $$aBirol, Melissa
000170409 700__ $$0(orcid)0000-0002-9138-6687$$aCremades, Nunilo$$uUniversidad de Zaragoza
000170409 700__ $$aMagzoub, Mazin
000170409 700__ $$aKumar, Sunil
000170409 7102_ $$11002$$2060$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Bioquímica y Biolog.Mole.
000170409 773__ $$g18, 843 (2026), [17 pp.]$$pSci.Transl.Med.$$tSCIENCE TRANSLATIONAL MEDICINE$$x1946-6234
000170409 8564_ $$s2076020$$uhttps://zaguan.unizar.es/record/170409/files/texto_completo.pdf$$yVersión publicada
000170409 8564_ $$s3491022$$uhttps://zaguan.unizar.es/record/170409/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000170409 909CO $$ooai:zaguan.unizar.es:170409$$particulos$$pdriver
000170409 951__ $$a2026-04-18-10:49:02
000170409 980__ $$aARTICLE