Nonantioxidant Tetramethoxystilbene Abrogates α-Synuclein-Induced Yeast Cell Death but Not That Triggered by the Bax or βa4 Peptide

Derf, Asma; Mudududdla, Ramesh; Akintade, Damilare; Williams, Ibidapo S.; Abdullaha, Mohd; Chaudhuri, Bhabatosh; Bharate, Sandip B.

Abstract

© 2018 American Chemical Society. The overexpression of α-synuclein (α-syn) and its aggregation is the hallmark of Parkinson's disease. The α-syn aggregation results in the formation of Lewy bodies that causes neuronal cell death. Therefore, the small molecules that can protect neuronal cells from α-syn toxicity or inhibit the aggregation of α-syn could emerge as anti-Parkinson agents. Herein, a library of methoxy-stilbenes was screened for their ability to restore the cell growth from α-syn toxicity, using a yeast strain that stably expresses two copies of a chromosomally integrated human α-syn gene. Tetramethoxy-stilbene 4s, a nonantioxidant, was the most capable of restoring cell growth. It also rescues the more toxic cells that bear three copies of wild-type or A53T-mutant α-syn, from cell growth block. Its EC50 values for growth restoration of the 2-copy wild-type and the 3-copy mutant α-syn strains are 0.95 and 0.35 μM, respectively. Stilbene 4s mitigates mitochondrial membrane potential loss, negates ROS production, and prevents nuclear DNA-fragmentation, all hallmarks of apoptosis. However, 4s does not rescue cells from the death-inducing effects of Bax and βA4, which suggest that 4s specifically inhibits α-syn-mediated toxicity in the yeast. Our results signify that simultaneous use of multiple yeast-cell-based screens can facilitate revelation of compounds that may have the potential for further investigation as anti-Parkinson's agents.

• Journal Article Type: Article
• Acceptance Date: Aug 1, 2018
• Publication Date: Aug 31, 2018
• Deposit Date: Aug 7, 2018
• Publicly Available Date: Aug 30, 2018
• Journal: ACS Omega
• Electronic ISSN: 2470-1343
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 3
• Issue: 8
• Pages: 9513-9532
• DOI: https://doi.org/10.1021/acsomega.8b01154
• Keywords: α-synuclein; tetramethoxystilbene; cell death; Bax; βA4 peptide; Parkinson’s disease
• Public URL: https://uwe-repository.worktribe.com/output/862762
• Publisher URL: http://dx.doi.org/10.1021/acsomega.8b01154
• Related Public URLs: http://pubs.acs.org.
• Additional Information: Additional Information : This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes. The final publication can be accessed here: http://dx.doi.org/10.1021/acsomega.8b01154
• Contract Date: Aug 7, 2018