Foldamers reveal and validate therapeutic targets associated with toxic α-synuclein self-assembly.

Autor: Ahmed J; Molecular and Cellular Biophysics Program, University of Denver, Denver, CO, 80210, USA.; The Knoebel Institute for Healthy Aging, University of Denver, Denver, CO, 80210, USA., Fitch TC; The Knoebel Institute for Healthy Aging, University of Denver, Denver, CO, 80210, USA.; Department of Chemistry and Biochemistry, University of Denver, Denver, CO, 80210, USA., Donnelly CM; The Knoebel Institute for Healthy Aging, University of Denver, Denver, CO, 80210, USA.; Department of Chemistry and Biochemistry, University of Denver, Denver, CO, 80210, USA., Joseph JA; The Knoebel Institute for Healthy Aging, University of Denver, Denver, CO, 80210, USA.; Department of Chemistry and Biochemistry, University of Denver, Denver, CO, 80210, USA., Ball TD; The Knoebel Institute for Healthy Aging, University of Denver, Denver, CO, 80210, USA.; Department of Chemistry and Biochemistry, University of Denver, Denver, CO, 80210, USA., Bassil MM; The Knoebel Institute for Healthy Aging, University of Denver, Denver, CO, 80210, USA.; Department of Chemistry and Biochemistry, University of Denver, Denver, CO, 80210, USA., Son A; The Knoebel Institute for Healthy Aging, University of Denver, Denver, CO, 80210, USA.; Department of Chemistry and Biochemistry, University of Denver, Denver, CO, 80210, USA., Zhang C; Department of Biological Sciences, University of Denver, Denver, CO, 80210, USA., Ledreux A; The Knoebel Institute for Healthy Aging, University of Denver, Denver, CO, 80210, USA., Horowitz S; Molecular and Cellular Biophysics Program, University of Denver, Denver, CO, 80210, USA.; The Knoebel Institute for Healthy Aging, University of Denver, Denver, CO, 80210, USA.; Department of Chemistry and Biochemistry, University of Denver, Denver, CO, 80210, USA., Qin Y; Department of Biological Sciences, University of Denver, Denver, CO, 80210, USA., Paredes D; The Knoebel Institute for Healthy Aging, University of Denver, Denver, CO, 80210, USA., Kumar S; Molecular and Cellular Biophysics Program, University of Denver, Denver, CO, 80210, USA. sunil.kumar97@du.edu.; The Knoebel Institute for Healthy Aging, University of Denver, Denver, CO, 80210, USA. sunil.kumar97@du.edu.; Department of Chemistry and Biochemistry, University of Denver, Denver, CO, 80210, USA. sunil.kumar97@du.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 Apr 27; Vol. 13 (1), pp. 2273. Date of Electronic Publication: 2022 Apr 27.
DOI: 10.1038/s41467-022-29724-4
Abstrakt: Parkinson's 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 (αS) into non-functional amyloid structures. One of the potential therapeutic interventions against PD is the effective inhibition of αS aggregation. However, the bottleneck towards achieving this goal is the identification of αS domains/sequences that are essential for aggregation. Using a protein mimetic approach, we have identified αS sequences-based targets that are essential for aggregation and will have significant therapeutic implications. An extensive array of in vitro, ex vivo, and in vivo assays is utilized to validate αS 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 αS aggregation, which will pave the way for effective treatments for PD.
(© 2022. The Author(s).)
Databáze: MEDLINE
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