期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 103, 期 39, 页码 14367-14372出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0602348103
关键词
Drosophila; Huntington's disease; in vitro; elongation kinetics; amyloid
资金
- NCI NIH HHS [CA 62203, P30 CA062203] Funding Source: Medline
- NIA NIH HHS [R01 AG019322, R01 AG 19322] Funding Source: Medline
- NINDS NIH HHS [R01 NS045283, NS 45283] Funding Source: Medline
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 HID.
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