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Citation
Slepko, N., Bhattacharyya, A.M., Jackson, G.R., Steffan, J.S., Marsh, J.L., Thompson, L.M., Wetzel, R. (2006). Normal-repeat-length polyglutamine peptides accelerate aggregation nucleation and cytotoxicity of expanded polyglutamine proteins.  Proc. Natl. Acad. Sci. U.S.A. 103(39): 14367--14372.
FlyBase ID
FBrf0193151
Publication Type
Research paper
Abstract

The dependence of disease risk and age-of-onset on expanded CAG repeat length in diseases like Huntington's disease (HD) is well established and correlates with the repeat-length-dependent nucleation kinetics of polyglutamine (polyGln) aggregation. The wide variation in ages of onset among patients with the same repeat length, however, suggests a role for modifying factors. Here we describe the ability of normal-length polyGln repeat sequences to greatly accelerate the nucleation kinetics of an expanded polyGln peptide. We find that normal-length polyGln peptides enhance the in vitro nucleation kinetics of a Q(47) peptide in a concentration-dependent and repeat-length-dependent manner. In vivo, we show that coexpression of a Q(20) sequence in a Drosophila model of HD expressing Htt exon 1 protein with an Q(93) repeat accelerates both aggregate formation and neurotoxicity. The accelerating effect of short polyGln peptides is attributable to the promiscuity of polyGln aggregate elongation and reflects the intimate relationship between nucleus formation and early elongation events in establishing nucleation kinetics. The results suggest that the overall state of the polyGln protein network in a cellular environment may have a profound effect on the toxic consequences of polyGln expansion and thus may serve as a genetic modifier of age of onset in HD.

PubMed ID
PubMed Central ID
PMC1599969 (PMC) (EuropePMC)
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    Language of Publication
    English
    Additional Languages of Abstract
    Parent Publication
    Publication Type
    Journal
    Abbreviation
    Proc. Natl. Acad. Sci. U.S.A.
    Title
    Proceedings of the National Academy of Sciences of the United States of America
    Publication Year
    1915-
    ISBN/ISSN
    0027-8424
    Data From Reference
    Alleles (3)
    Genes (3)
    Human Disease Models (1)
    Transgenic Constructs (3)