Expression of polyalanine stretches induces mitochondrial dysfunction

Kazuya Toriumi, Yoko Oma, Yoshihiro Kino, Eugene Futai, Noboru Sasagawa, Shoichi Ishiura

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19 Citations (Scopus)


In recent years, several novel types of disorders have been characterized, including what have been termed polyalanine diseases, in which patients have expanded triplet repeats in specific genes, resulting in the translation of aberrantly elongated polyalanine stretches. In this study, we showed that yellow fluorescent protein (YFP)-fused elongated polyalanine stretches localized exclusively to the cytoplasm and formed aggregates. Additionally, the polyalanine stretches themselves were toxic. We sought to identify proteins that bound directly to the polyalanine stretches, as factors that might be involved in triggering cell death. Many mitochondrial proteins were identified as polyalanine-binding proteins. We showed that one of the identified proteins, succinate dehydrogenase subunit A, was decreased in the mitochondria of cells expressing polyalanine stretches; as a result, succinate oxidative activity was decreased. Furthermore, the polyalanine stretches also associated directly with mitochondria. This suggests that polyalanine stretches might directly induce cell death. Additionally, the mitochondrial membrane potential was reduced in cells expressing polyalanine stretches. We propose a novel mechanism by which polyalanine stretches may cause cytotoxicity through mitochondrial dysfunction. This may be a common mechanism underlying the pathogenesis of all polyalanine diseases.

Original languageEnglish
Pages (from-to)1529-1537
Number of pages9
JournalJournal of Neuroscience Research
Issue number7
Publication statusPublished - 2008 May 15


  • Mitochondria
  • Mitochondrial membrane potential
  • Polyalanine
  • Succinate dehydrogenase


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