Improvement of spinal muscular atrophy via correction of the SMN2 splicing defect by Brucea javanica (L.) Merr. extract and Bruceine D = 아담자 및 bruceine D의 척수성 근위축 개선효능
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- Improvement of spinal muscular atrophy via correction of the SMN2 splicing defect by Brucea javanica (L.) Merr. extract and Bruceine D = 아담자 및 bruceine D의 척수성 근위축 개선효능
- Jiyeon Baek; Hyejeong Jeong; Yeongwook Ham; Yang Hee Jo; Miri Choi; Mingu Kang; Bora Son; Sangho Choi; Hyung Won Ryu; Janghwan Kim; H Shen; K Sydara; Sang Woo Lee; Soo Yong Kim; S B Han; Sei-Ryang Oh; Sungchan Cho
- Bibliographic Citation
- Phytomedicine, vol. 65, pp. 153089-153089
- Publication Year
Spinal muscular atrophy (SMA) is a rare neuromuscular disease and a leading genetic cause of infant mortality. SMA is caused primarily by the deletion of the survival motor neuron 1 (SMN1) gene, which leaves the duplicate gene SMN2 as the sole source of SMN protein. The splicing defect (exon 7 skipping) of SMN2 leads to an insufficient amount of SMN protein. Therefore, correcting this SMN2 splicing defect is considered to be a promising approach for the treatment of SMA.
This study aimed to identify active compounds and extracts from plant resources to rescue SMA phenotypes through the correction of SMN2 splicing.
Of available plant resources, candidates with SMA-related traditional medicine information were selected for screening using a robust luciferase-based SMN2 splicing reporter. Primary hits were further evaluated for their ability to correct the splicing defect and resultant increase of SMN activity in SMA patient-derived fibroblasts. Confirmed hits were finally tested to determine the beneficial effects on the severe Δ7 SMA mouse.
SMN2 splicing was analyzed using a luciferase-based SMN2 splicing reporter and subsequent RT-PCR of SMN2 mRNAs. SMA phenotypes were evaluated by the survival, body weights, and righting reflex of Δ7 SMA mice.
In a screen of 492 selected plant extracts, we found that Brucea javanica extract and its major constituent Bruceine D have SMN2 splicing-correcting activity. Their ability to correct the splicing defect and the resulting increased SMN activity were further confirmed in SMA fibroblasts. Importantly, both B. javanica and Bruceine D noticeably improved the phenotypic defects, especially muscle function, in SMA mice. Reduced expression of heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) contributed to the correction of splicing by B. javanica.
Our work revealed that B. javanica and Bruceine D correct the SMN2 splicing defect and improve the symptoms of SMA in mice. These resources will provide another possibility for development of a plant-derived SMA drug candidate.
- Alternative splicingBrucea javanica, Bruceine DNeuromuscular diseaseSpinal muscular atrophy (SMA)Splicing modulator
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- Ochang Branch Institute > Division of National Bio-Infrastructure > International Biological Material Research Center > 1. Journal Articles
Ochang Branch Institute > Natural Product Research Center > 1. Journal Articles
Division of Research on National Challenges > Stem Cell Convergenece Research Center > 1. Journal Articles
Ochang Branch Institute > 1. Journal Articles
Ochang Branch Institute > Nucleic Acid Therapeutics Research Center > 1. Journal Articles
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