![[feed]](/style/images/feed-icon-14x14.png){kind=icon}
Tools
Tools
| Item Type: | Article |
|---|---|
| Title: | Foldamers rescue synucleinopathy phenotypes in multiple in vitro and in vivo models |
| Creators: |
Dohoney, Ryan A.  ORCID: https://orcid.org/0000-0002-0190-8665, Palanikumar, L. ORCID: https://orcid.org/0000-0002-2639-0436, Oldani, Emily ORCID: https://orcid.org/0009-0006-5430-0270, Baysah, Charles Zuwu ORCID: https://orcid.org/0000-0003-0657-0461, Joseph, Johnson A. ORCID: https://orcid.org/0000-0002-0415-3122, Polanco, David ORCID: https://orcid.org/0000-0002-0005-6712, Santos-Otte, Paula ORCID: https://orcid.org/0009-0009-4556-0574, Stillman, Nicholas H. ORCID: https://orcid.org/0000-0002-8353-7684, Corcoran, Peter, Ball, Tyler D. ORCID: https://orcid.org/0000-0001-9602-0329, Fitch, Tessa C., Ahmed, Jemil, Ogbonna-Ukuku, Ifunayachi ORCID: https://orcid.org/0009-0001-3818-5421, Reynolds Caicedo, Kevin M. ORCID: https://orcid.org/0009-0000-4688-0144, Liu, Ying, Leehey, Maureen A., Linseman, Daniel A. ORCID: https://orcid.org/0000-0001-8774-1976, Paredes, Daniel A. ORCID: https://orcid.org/0000-0002-9635-8001, Birol, Melissa ORCID: https://orcid.org/0000-0003-3397-8446, Cremades, Nunilo ORCID: https://orcid.org/0000-0002-9138-6687, Magzoub, Mazin ORCID: https://orcid.org/0000-0003-3414-6617 and Kumar, Sunil ORCID: https://orcid.org/0000-0001-5472-4619
|
| Abstract: | Synucleinopathies 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 (K(d) = 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. |
| Keywords: | Alpha-Synuclein, Animal Disease Models, Blood-Brain Barrier, Induced Pluripotent Stem Cells, Neurons, Phenotype, Synucleinopathies, Animals, Mice, Worms, Caenorhabditis elegans |
| Source: | Science Translational Medicine |
| ISSN: | 1946-6234 |
| Publisher: | American Association for the Advancement of Science |
| Volume: | 18 |
| Number: | 843 |
| Page Range: | eadu1050 |
| Date: | 1 April 2026 |
| Official Publication: | https://doi.org/10.1126/scitranslmed.adu1050 |
| PubMed: | View item in PubMed |
Repository Staff Only: item control page
