Radicicol rescues yeast cell death triggered by expression of human α-synuclein and its A53T mutant, but not by human βA4 peptide and proapoptotic protein bax
Autor: | Bhabatosh Chaudhuri, Shreyans K. Jain, Asma Derf, Shilpa Amit Verekar, Sunil K. Deshmukh, Sandip B. Bharate |
---|---|
Rok vydání: | 2018 |
Předmět: |
Programmed cell death
Mutant Sordariales Apoptosis Saccharomyces cerevisiae 01 natural sciences Biochemistry Hsp90 inhibitor chemistry.chemical_compound Drug Discovery Humans Molecular Biology bcl-2-Associated X Protein Membrane Potential Mitochondrial Amyloid beta-Peptides biology 010405 organic chemistry Chemistry Organic Chemistry Free Radical Scavengers Hsp90 Yeast 0104 chemical sciences Cell biology Hsp70 Radicicol Mitochondria Molecular Docking Simulation 010404 medicinal & biomolecular chemistry Mutation biology.protein alpha-Synuclein Macrolides Reactive Oxygen Species Protein Binding |
Zdroj: | Bioorganic chemistry. 85 |
ISSN: | 1090-2120 |
Popis: | Aggregation/misfolding of α-synuclein and βA4 proteins cause neuronal cell death (NCD) associated with Parkinson's and Alzheimer's disease. It has been suggested that a heat shock protein-90 (Hsp90) inhibitor can prevent NCD by activating the heat shock transcription factor-1 which, in turn, upregulates molecular chaperones such as Hsp70 that targets aggregated/misfolded proteins for refolding/degradation. We have isolated radicicol, an Hsp90 inhibitor, from a fungus occurring in the crevices of marble rocks of Central India. Radicicol, which was found to be a strong antioxidant, was tested for its ability to rescue yeast cells from death induced by expression of wild-type α-synuclein, its more toxic A53T mutant, and βA4. It effectively overcomes wild-type/mutant α-synuclein mediated yeast cell death, concomitantly diminishes ROS levels, reverses mitochondrial dysfunction and prevents nuclear DNA-fragmentation, a hallmark of apoptosis. Surprisingly however, radicicol is unable to rescue yeast cells from death triggered by expression of secreted βA4. Moreover, although radicicol acts as an antioxidant it fails to prevent yeast cell death inflicted by the proapoptotic protein, Bax. Our results indicate that radicicol specifically targets aggregated/misfolded α-synuclein's toxicity and opens up the possibility of using multiple yeast assays to screen natural product libraries for compounds that would unambiguously target α-synuclein aggregation/misfolding. |
Databáze: | OpenAIRE |
Externí odkaz: |