Foldamers Reveal and Validate Novel Therapeutic Targets Associated with Toxic α-Synuclein Self-Assembly

Ahmed, J.; Fitch, T. C.; Donnelly, C. M.; Joseph, J. A.; Bassil, M. M.; Son, A.; Zhang, C.; Ledreux, A.; Horowitz, S.; Qin, Y.; Paredes, D.; Kumar, S.

doi:10.1101/2021.05.08.443146

bioRxiv · 10.1101/2021.05.08.443146

Foldamers Reveal and Validate Novel Therapeutic Targets Associated with Toxic α-Synuclein Self-Assembly

Ahmed, J.·Fitch, T. C.·Donnelly, C. M.·Joseph, J. A.·Bassil, M. M.·Son, A.·Zhang, C.·Ledreux, A.·Horowitz, S.·Qin, Y.·Paredes, D.·Kumar, S.

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Abstract

Parkinsons disease (PD) is a progressive neurodegenerative disorder for which there is no successful prevention or intervention. The pathological hallmark for PD involves the self-assembly of functional Alpha-Synuclein (S) into non-functional amyloid structures. One of the potential therapeutic interventions against PD is the effective inhibition of S aggregation. However, the bottleneck towards achieving this goal is the identification of S domains/sequences that are essential for aggregation. Using a protein mimetic approach, we have identified S sequences-based novel targets that are essential for aggregation and will have significant therapeutic implications. An extensive array of in vitro, ex vivo, and in vivo assays was utilized to validate S sequences and their structural characteristics that are essential for aggregation and propagation of PD phenotypes. The study aids in developing significant mechanistic and therapeutic insights into various facets of S aggregation, which will pave the way for novel and effective treatments for PD.

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Ahmed, J., Fitch, T. C., Donnelly, C. M., Joseph, J. A., Bassil, M. M., Son, A., Zhang, C., Ledreux, A., Horowitz, S., Qin, Y., Paredes, D., Kumar, S.. 2021-05-08. Foldamers Reveal and Validate Novel Therapeutic Targets Associated with Toxic α-Synuclein Self-Assembly. https://doi.org/10.1101/2021.05.08.443146

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