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

Cited 4 time in scopus
Metadata Downloads
Title
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
Author(s)
Jiyeon Baek; Hyejeong Jeong; Yeongwook Ham; Yang Hee Jo; Miri Choi; Mingu Kang; Bora Son; Sangho ChoiHyung Won RyuJanghwan Kim; H Shen; K Sydara; Sang Woo LeeSoo Yong Kim; S B Han; Sei-Ryang OhSungchan Cho
Bibliographic Citation
Phytomedicine, vol. 65, pp. 153089-153089
Publication Year
2019
Abstract
BACKGROUND: 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. PURPOSE: This study aimed to identify active compounds and extracts from plant resources to rescue SMA phenotypes through the correction of SMN2 splicing. STUDY DESIGN: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
Keyword
Alternative splicingBrucea javanica, Bruceine DNeuromuscular diseaseSpinal muscular atrophy (SMA)Splicing modulator
ISSN
0944-7113
Publisher
Elsevier
DOI
http://dx.doi.org/10.1016/j.phymed.2019.153089
Type
Article
Appears in Collections:
Ochang Branch Institute > Division of Bioinfrastructure > International Biological Material Research Center > 1. Journal Articles
Ochang Branch Institute > Natural Medicine 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
Files in This Item:
  • There are no files associated with this item.


Items in OpenAccess@KRIBB are protected by copyright, with all rights reserved, unless otherwise indicated.