Normal-repeat-length polyglutamine peptides accelerate aggregation nucleation and cytotoxicity of expanded polyglutamine proteins

摘要

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 (polyGIn) 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 polyGIn repeat sequences to greatly accelerate the nucleation kinetics of an expanded polyGIn peptide. We find that normal-length polyGIn 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 polyGIn peptides is attributable to the promiscuity of polyGIn 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 polyGIn protein network in a cellular environment may have a profound effect on the toxic consequences of polyGIn expansion and thus may serve as a genetic modifier of age of onset in HD.