Normal-Repeat-Length Polyglutamine Peptides Accelerate Aggregation Nucleation and Cytotoxicity of Expanded Polyglutamine Proteins

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 pati...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2006-09, Vol.103 (39), p.14367-14372
Main Authors: Slepko, Natalia, Bhattacharyya, Anusri M., Jackson, George R., Steffan, Joan S., Marsh, J. Lawrence, Thompson, Leslie Michels, Wetzel, Ronald
Format: Article
Language:English
Subjects:
Aggregation
Amyloids
Animals
Biological Sciences
Cell aggregates
Cell Death
Drosophila
Drosophila melanogaster - cytology
Enzyme kinetics
Eye - cytology
Eye - pathology
Gene expression
Genetic disorders
Humans
Huntington disease
Kinetics
Models, Animal
Monomers
Neurodegenerative Diseases - chemically induced
Nuclear inclusions
Nucleation
Peptides
Peptides - chemistry
Peptides - metabolism
Peptides - toxicity
Photoreceptors
Protein Structure, Quaternary
Proteins
Proteins - chemistry
Repetitive Sequences, Amino Acid
Structure-Activity Relationship
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Summary: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 concentrationdependent 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 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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0602348103