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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.

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


Authors

Asma Derf

Ramesh Mudududdla

Damilare Akintade

Mohd Abdullaha

Bhabatosh Chaudhuri

Sandip B. Bharate



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.

Citation

Derf, A., Mudududdla, R., Akintade, D., Williams, I. S., Abdullaha, M., Chaudhuri, B., & Bharate, S. B. (2018). Nonantioxidant Tetramethoxystilbene Abrogates α-Synuclein-Induced Yeast Cell Death but Not That Triggered by the Bax or βa4 Peptide. ACS Omega, 3(8), 9513-9532. https://doi.org/10.1021/acsomega.8b01154

Journal Article Type Article
Acceptance Date Aug 1, 2018
Publication Date Aug 31, 2018
Deposit Date Aug 7, 2018
Publicly Available Date Mar 28, 2024
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

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