Genetics Of Nervous System DiseasesAmino acid sequences flanking polyglutamine stretches influence their potential for aggregate formationNozaki, Kenkichi; Onodera, OsamuCA; Takano, Hiroki; Tsuji, ShojiAuthor Information Department of Neurology, Brain Research Institute, Niigata University, 1-757 Asahimachi-dori, Niigata 951-8585, Japan CACorresponding Author Received 9 July 2001; accepted 15 August 2001 NeuroReport: October 29th, 2001 - Volume 12 - Issue 15 - p 3357-3364 Buy 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. © 2001 Lippincott Williams & Wilkins, Inc.