Expression of N19S-SOD1, an SOD1 mutant found in sporadic amyotrophic lateral sclerosis patients, induces low-grade motoneuronal toxicity

Yuji Obata, Takako Niikura, Kohsuke Kanekura, Yuichi Hashimoto, Masaoki Kawasumi, Yoshiko Kita, Sadakazu Aiso, Masaaki Matsuoka, Ikuo Nishimoto

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11 Citations (Scopus)

Abstract

Amyotrophic lateral sclerosis (ALS) is the most common fatal motor neuron disease. It has been generally accepted that the proapoptotic property of the familial ALS (FALS)-linked mutant SOD1 genes plays an important role in the pathogenesis of some FALS cases. We found here that expression of N19S-SOD1, a novel SOD1 mutant originally found in a sporadic ALS patient, induces lower grade death in NSC34 cells than FALS-linked mutant SOD1. In agreement, intracytoplasmic aggregate formation and SOD1 polymerization are less prominently induced by ectopic expression of N19S-SOD1 than FALS-linked mutant SOD1. We further found that additional cell stresses, such as inhibition of proteasomal activity or up-regulation of intracellular oxidative stress, enhance N19S-SOD1-induced aggregate formation and polymerization of N19S-SOD1. Such analysis of the intracellular polymerization and the ubiquitination of N19S-SOD1 have further suggested that it is recognized as a misfolded protein, like FALS-linked mutant SOD1, whereas wild-type SOD1 is not. Altogether, it is speculated that the N19S mutation of SOD1 in cooperation with associated cell stresses contributes to the onset of ALS as a risk factor.

Original languageEnglish
Pages (from-to)720-729
Number of pages10
JournalJournal of neuroscience research
Volume81
Issue number5
DOIs
Publication statusPublished - 2005 Sep 1

Keywords

  • ALS
  • N19S-SOD1
  • Neuronal cell death
  • Neuroprotection
  • SOD1

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

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    Obata, Y., Niikura, T., Kanekura, K., Hashimoto, Y., Kawasumi, M., Kita, Y., Aiso, S., Matsuoka, M., & Nishimoto, I. (2005). Expression of N19S-SOD1, an SOD1 mutant found in sporadic amyotrophic lateral sclerosis patients, induces low-grade motoneuronal toxicity. Journal of neuroscience research, 81(5), 720-729. https://doi.org/10.1002/jnr.20594