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

doi:10.1073/pnas.0602348103

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

Departments of ^†Psychiatry and Human Behavior and
^‖Biological Chemistry, University of California, Irvine, CA 92697-4260;
^‡Graduate School of Medicine, University of Tennessee, Knoxville, TN 37920;
^§Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095; and
^¶Developmental Biology Center and Department of Developmental and Cell Biology, University of California, Irvine, CA 92697-2300

Edited by Sue Hengren Wickner, National Institutes of Health, Bethesda, MD, and approved August 1, 2006 (received for review March 22, 2006)

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 Q₄₇ peptide in a concentration-dependent and repeat-length-dependent manner. In vivo, we show that coexpression of a Q₂₀ sequence in a Drosophila model of HD expressing Htt exon 1 protein with an Q₉₃ 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.

Footnotes

^††To whom correspondence should be sent at the present address:
Department of Structural Biology, University of Pittsburgh School of Medicine, 2044 Biomedical Science Tower 3, 3501 Fifth Avenue, Pittsburgh, PA 15260.
E-mail: rwetzel{at}pitt.edu
Author contributions: N.S. and A.M.B. contributed equally to this work; N.S., A.M.B., G.R.J., J.S.S., J.L.M., L.M.T., and R.W. designed research; N.S. and A.M.B. performed research; G.R.J. contributed new reagents/analytic tools; N.S., A.M.B., G.R.J., J.S.S., J.L.M., L.M.T., and R.W. analyzed data; and N.S., A.M.B., G.R.J., J.S.S., J.L.M., L.M.T., and R.W. wrote the paper.
The authors declare no conflict of interest.
This paper was submitted directly (Track II) to the PNAS office.