title: Amino acid sequences flanking polyglutamine stretches influence their potential for aggregate formation.
abstract: Expanded polyglutamine stretches have been shown to form aggregates and to be toxic to cells. In this study, we hypothesized that amino acid sequences flanking the polyglutamine stretches influence the aggregate formation potential of these stretches. Green fluorescent protein (GFP) fusion proteins containing glutamine repeats of various lengths and a fixed number of flanking amino acids of ataxin-2, huntingtin, dentatorubral-pallidoluysian atrophy protein (DRPLAP) or ataxin-3 were transiently expressed in COS-7 cells. The aggregate formation potential of ataxin-2 and DRPLAP increased in a CAG-repeat-length-dependent manner, with a threshold between 34 and 36. Truncated ataxin-2-Q56-GFP and truncated huntingtin-Q56-GFP showed a significantly higher aggregate formation potential than truncated DRPLAP-Q56-GFP or truncated ataxin-3-Q56-GFP. These results are in agreement with the clinical observation that ages of disease onset in patients with spinocerebellar ataxia type 2 or Huntington's disease are lower than those in patients with DRPLA or Machado-Joseph disease having expanded CAG repeats of the same length. Furthermore, mutagenesis of the flanking sequence of ataxin-2 markedly reduced its aggregate formation potential. These results indicate that the amino acid sequences flanking the polyglutamine stretches significantly influence their aggregate formation potential.
authors.affiliation: Department of Neurology, Brain Research Institute, Niigata University, 1-757 Asahimachi-dori, Niigata 951-8585, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Nozaki
authors.forename: O
authors.initials: O
authors.lastname: Onodera
authors.forename: H
authors.initials: H
authors.lastname: Takano
authors.forename: S
authors.initials: S
authors.lastname: Tsuji
mesh_terms: D000595:Amino Acid Sequence / Q000235:genetics; D000818:Animals; D000067699:Ataxin-3; D000067528:Ataxins; D019556:COS Cells; D002490:Central Nervous System / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D049452:Green Fluorescent Proteins; D002479:Inclusion Bodies / Q000235:genetics / Q000378:metabolism*; D007202:Indicators and Reagents / Q000378:metabolism; D008164:Luminescent Proteins / Q000235:genetics; D016297:Mutagenesis, Site-Directed / Q000502:physiology*; D009154:Mutation / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D014176:Protein Biosynthesis; D017510:Protein Folding; D017433:Protein Structure, Secondary / Q000235:genetics; D011506:Proteins / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics; D012097:Repressor Proteins; D014162:Transfection; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
chemical_list: D000067528:Ataxins; D007202:Indicators and Reagents; D008164:Luminescent Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D011506:Proteins; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; C095278:atrophin-1; D049452:Green Fluorescent Proteins; C097188:polyglutamine; C092341:ATXN3 protein, human; D000067699:Ataxin-3