2-Butoxytetrahydrofuran, Isolated from Holothuria scabra, Attenuates Aggregative and Oxidative Properties of α-Synuclein and Alleviates Its Toxicity in a Transgenic Caenorhabditis elegans Model of Parkinson’s Disease
Issued Date
2024-01-01
Resource Type
eISSN
19487193
Scopus ID
2-s2.0-85192830770
Pubmed ID
38726817
Journal Title
ACS Chemical Neuroscience
Rights Holder(s)
SCOPUS
Bibliographic Citation
ACS Chemical Neuroscience (2024)
Suggested Citation
Promtang S., Sanguanphun T., Chalorak P., Pe L.S., Niamnont N., Sobhon P., Meemon K. 2-Butoxytetrahydrofuran, Isolated from Holothuria scabra, Attenuates Aggregative and Oxidative Properties of α-Synuclein and Alleviates Its Toxicity in a Transgenic Caenorhabditis elegans Model of Parkinson’s Disease. ACS Chemical Neuroscience (2024). doi:10.1021/acschemneuro.4c00008 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/98390
Title
2-Butoxytetrahydrofuran, Isolated from Holothuria scabra, Attenuates Aggregative and Oxidative Properties of α-Synuclein and Alleviates Its Toxicity in a Transgenic Caenorhabditis elegans Model of Parkinson’s Disease
Corresponding Author(s)
Other Contributor(s)
Abstract
Aggregative α-synuclein and incurring oxidative stress are pivotal cascading events, leading to dopaminergic (DAergic) neuronal loss and contributing to clinical manifestations of Parkinson’s disease (PD). Our previous study demonstrated that 2-butoxytetrahydrofuran (2-BTHF), isolated from Holothuria scabra (H. scabra), could inhibit amyloid-β aggregation and its ensuing toxicity, which leads to Alzheimer’s disease. In the present study, we found that 2-BTHF also attenuated the aggregative and oxidative activities of α-synuclein and lessened its toxicity in a transgenic Caenorhabditis elegans (C. elegans) PD model. Such worms treated with 100 μM of 2-BTHF showed substantial reductions in α-synuclein accumulation and DAergic neurodegeneration. Mechanistically, 2-BTHF, at this concentration, significantly decreased aggregation of monomeric α-synuclein and restored locomotion and dopamine-dependent behaviors. Molecular docking exhibited potential bindings of 2-BTHF to HSF-1 and DAF-16 transcription factors. Additionally, 2-BTHF significantly increased the mRNA transcripts of genes encoding proteins involved in proteostasis, including the molecular chaperones hsp-16.2 and hsp-16.49, the ubiquitination/SUMOylation-related ubc-9 gene, and the autophagy-related genes atg-7 and lgg-1. Transcriptomic profiling revealed an additional mechanism of 2-BTHF in α-synuclein-expressing worms, which showed upregulation of PPAR signaling cascades that mediated fatty acid metabolism. 2-BTHF significantly restored lipid deposition, upregulated the fat-7 gene, and enhanced gcs-1-mediated glutathione synthesis in the C. elegans PD model. Taken together, this study demonstrated that 2-BTHF could abrogate aggregative and oxidative properties of α-synuclein and attenuate its toxicity, thus providing a possible therapeutic application for the treatment of α-synuclein-induced PD.
