Securinine enhances SMN2 exon 7 inclusion in spinal muscular atrophy cells

Yu Chia Chen, Jan-Gowth Chang, Ting Yuan Liu, Yuh-Jyh Jong, Wei-Lin Cheng, Chung-Yee Yuo

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by the degeneration of motor neurons in the spinal cord, leading to muscular atrophy. SMA is caused by deletions or mutations in the survival motor neuron gene (SMN1) on chromosome 5q13. A second copy of the SMN gene (SMN2) also exists on chromosome 5, and both genes can produce functional protein. However, due to alternative splicing of the exon 7, the majority of SMN protein produced by SMN2 is truncated and unable to compensate for the loss of SMN1. Increasing full-length SMN protein production by promoting the exon 7 inclusion in SMN2 mRNA or increasing SMN2 gene transcription could be a therapeutic approach for SMA. In this study, we screened for the compounds that enhance SMN2 exon 7 inclusion by using SMN2 minigene-luciferase reporter system. We found that securinine can increase luciferase activity, indicating that securinine promoted SMN2 exon 7 inclusion. In addition, securinine increased full-length SMN2 mRNA and SMN protein expression in SMA patient-derived lymphoid cell lines. To investigate the mechanism of securinine effect on SMN2 splicing, we compared the protein levels of relevant splicing factors between securinine-treated and untreated cells. We found that securinine downregulated hnRNP A1 and Sam68 and upregulated Tra2-b1 expression. However, securinine, unlike HDAC inhibitors, did not enhance tra2-b1 gene transcription, indicating a post-transcriptional mechanism for Tra2-b1 upregulation. Furthermore, we treated SMA-like mice with securinine by i.p. injection and found that securinine treatment increased SMN2 exon 7 inclusion and SMN protein expression in the brain and spinal cord. According to our results, securinine might have the potential to become a therapeutic drug for SMA disease. (C) 2017 Elsevier Masson SAS. All rights reserved.
Original languageEnglish
Pages (from-to)708-714
Number of pages7
JournalBIOMEDICINE & PHARMACOTHERAPY
Volume88
DOIs
StatePublished - Apr 2017

Keywords

  • Spinal muscular atrophy; Survival motor neuron gene; Securinine; Tra2-beta1
  • MOTOR-NEURON SMN; MESSENGER-RNA; SPLICING ENHANCER; DETERMINING GENE; SURVIVAL; PROTEIN; HTRA2-BETA-1; APOPTOSIS; EXPRESSION; PRODUCT

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    Chen, Y. C., Chang, J-G., Liu, T. Y., Jong, Y-J., Cheng, W-L., & Yuo, C-Y. (2017). Securinine enhances SMN2 exon 7 inclusion in spinal muscular atrophy cells. BIOMEDICINE & PHARMACOTHERAPY, 88, 708-714. https://doi.org/10.1016/j.biopha.2017.01.104