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| Item Type: | Article |
|---|---|
| Title: | Foldamers rescue synucleinopathy phenotypes in multiple in vitro and in vivo models |
| Creators Name: | Dohoney, Ryan A., Palanikumar, L., Oldani, Emily, Baysah, Charles Zuwu, Joseph, Johnson A., Polanco, David, Santos-Otte, Paula, Stillman, Nicholas H., Corcoran, Peter, Ball, Tyler D., Fitch, Tessa C., Ahmed, Jemil, Ogbonna-Ukuku, Ifunayachi, Reynolds Caicedo, Kevin M., Liu, Ying, Leehey, Maureen A., Linseman, Daniel A., Paredes, Daniel A., Birol, Melissa, Cremades, Nunilo, Magzoub, Mazin and Kumar, Sunil |
| 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 |
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