title: Expression of polyalanine stretches induces mitochondrial dysfunction.
abstract: 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 polya-lanine 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.
authors.affiliation: Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, Meguro-ku, Tokyo, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Toriumi
authors.forename: Yoko
authors.initials: Y
authors.lastname: Oma
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kino
authors.forename: Eugene
authors.initials: E
authors.lastname: Futai
authors.forename: Noboru
authors.initials: N
authors.lastname: Sasagawa
authors.forename: Shoichi
authors.initials: S
authors.lastname: Ishiura
mesh_terms: D000818:Animals; D001426:Bacterial Proteins; D019556:COS Cells / Q000648:ultrastructure; D002352:Carrier Proteins; D002522:Chlorocebus aethiops; D045304:Cytochromes c / Q000378:metabolism; D005434:Flow Cytometry / Q000379:methods; D005982:Glutathione Transferase / Q000378:metabolism; D008164:Luminescent Proteins; D013058:Mass Spectrometry / Q000379:methods; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D013347:Subcellular Fractions / Q000378:metabolism; D013385:Succinate Dehydrogenase / Q000378:metabolism; D014162:Transfection; D019680:Trinucleotide Repeat Expansion / Q000235:genetics / Q000502:physiology*
chemical_list: D001426:Bacterial Proteins; D002352:Carrier Proteins; D008164:Luminescent Proteins; D010455:Peptides; C054562:yellow fluorescent protein, Bacteria; C019529:polyalanine; D045304:Cytochromes c; D013385:Succinate Dehydrogenase; D005982:Glutathione Transferase