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Synergistic anti-apoptotic activity between Bcl-2 and SMN implicated in spinal muscular atrophy

Nature volume 390, pages 413–417 (1997)Cite this article

Abstract

Spinal muscular atrophy (SMA) is a motor neuron disease characterized by degeneration of the anterior horn cells of the spinal cord. It is a common fatal autosomal recessive disorder and linkage studies have identified two candidate genes, SMN (ref. 1) and NAIP (ref. 2), both on chromosome 5q13. Although NAIP protein is known to have an anti-apoptotic function3, the function of SMN has been unclear and it shows no significant sequence similarity to any other protein. The SMN gene is deleted or interrupted on both chromosomes in nearly all SMA patients1. Here we show that SMN interacts with Bcl-2, another anti-apoptotic protein4, and that co-expression of SMN with Bcl-2 confers a synergistic preventive effect against Bax-induced or Fas-mediated apoptosis, although SMN itself has only a weak anti-apoptotic activity. SMNY272C, which carries a missense mutation and was found in an SMA patient who exceptionally retained SMN on one allele1, exerts no synergism with Bcl-2. Furthermore, the product of a truncated transcript lacking exon 7, which was derived from an SMN gene carrying an intragenic mutation or from the SMN copy gene c BCD541 (ref. 1) retained in all SMA patients, had no synergistic activity but instead had a dominant-negative effect on full-length SMN. Our results indicate that an absent or decreased anti-apoptotic activity of SMN in concert with Bcl-2 underlies the pathogenesis of SMA.

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Figure 1: Co-immunoprecipitation of human Bcl-2 and SMN.
Figure 2: Intracellular localization of SMN protein.
Figure 3: Fluorescence microscope analysis of synergistic prevention of Bax-induced apoptosis by SMN and Bcl-2.
Figure 4: a, Per cent inhibition of Bax-induced apoptosis by hBcl-2, cBcl-2 and SMN.

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Acknowledgements

We thank J. Miyazaki, A. Shinohara and D. Y. Mason for their kind gifts of pCAGGS-BMG plasmid, pBTM116-RAD51 and anti-hBcl-2 mAb, respectively; T. Hachiya and M. Ikeda for their help in generating antibodies; and M. Hoffman for editorial assistance. This work was supported in part by grants for Scientific Research on Priority Areas and for COE Research from the Ministry of Education, Science, and Culture of Japan.

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  1. Hiromi Iwahashi, Yutaka Eguchi and Noriko Yasuhara: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medical Genetics, Biomedical Research Center Osaka University Medical School, 2-2 Yamadaoka, Suita, 565, Osaka, Japan

    Hiromi Iwahashi, Yutaka Eguchi, Noriko Yasuhara & Yoshihide Tsujimoto

  2. Second Department of Internal Medicine, Osaka University Medical School, 2-2 Yamadaoka, Suita, 565, Osaka, Japan

    Hiromi Iwahashi, Toshiaki Hanafusa & Yuji Matsuzawa

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  1. Hiromi Iwahashi
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Correspondence to Yoshihide Tsujimoto.

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Iwahashi, H., Eguchi, Y., Yasuhara, N. et al. Synergistic anti-apoptotic activity between Bcl-2 and SMN implicated in spinal muscular atrophy. Nature 390, 413–417 (1997). https://doi.org/10.1038/37144

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