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Prevention of polyglutamine oligomerization and neurodegeneration by the peptide inhibitor QBP1 in Drosophila.

Publication ,  Journal Article
Nagai, Y; Fujikake, N; Ohno, K; Higashiyama, H; Popiel, HA; Rahadian, J; Yamaguchi, M; Strittmatter, WJ; Burke, JR; Toda, T
Published in: Hum Mol Genet
June 1, 2003

Polyglutamine (polyQ) diseases are a growing class of inherited neurodegenerative diseases including Huntington's disease, which are caused by abnormal expansions of the polyQ stretch in each unrelated disease protein. The expanded polyQ stretch is thought to confer toxic properties on the disease proteins through alteration of their conformation leading to pathogenic protein-protein interactions including oligomerization and/or aggregation. Hypothesizing that molecules with selective binding affinity to the expanded polyQ stretch may interfere with the pathogenic properties, we previously identified Polyglutamine Binding Peptide 1 (QBP1) from combinatorial peptide phage display libraries. We show here that a tandem repeat of the inhibitor peptide QBP1, (QBP1)(2), significantly suppresses polyQ aggregation and polyQ-induced neurodegeneration in the compound eye of Drosophila polyQ disease models, which express the expanded polyQ protein under the eye specific promoter. Most importantly, (QBP1)(2) expression dramatically rescues premature death of flies expressing the expanded polyQ protein in the nervous system, resulting in the dramatic increase of the median life span from 5.5 to 52 days. These results suggest that QBP1 can prevent polyQ-induced neurodegeneration in vivo. We propose that QBP1 prevents polyQ oligomerization and/or aggregation either by altering the toxic conformation of the expanded polyQ stretch, or by simply competing with the expanded polyQ stretches for binding to other expanded polyQ proteins. The peptide inhibitor QBP1 is a promising candidate with great potential as a therapeutic molecule against the currently untreatable polyQ diseases.

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Published In

Hum Mol Genet

DOI

ISSN

0964-6906

Publication Date

June 1, 2003

Volume

12

Issue

11

Start / End Page

1253 / 1259

Location

England

Related Subject Headings

  • Promoter Regions, Genetic
  • Peptides
  • Oligopeptides
  • Neurodegenerative Diseases
  • Nervous System
  • Humans
  • Genetics & Heredity
  • Embryo, Nonmammalian
  • Drosophila
  • Disease Models, Animal
 

Citation

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Nagai, Y., Fujikake, N., Ohno, K., Higashiyama, H., Popiel, H. A., Rahadian, J., … Toda, T. (2003). Prevention of polyglutamine oligomerization and neurodegeneration by the peptide inhibitor QBP1 in Drosophila. Hum Mol Genet, 12(11), 1253–1259. https://doi.org/10.1093/hmg/ddg144
Nagai, Yoshitaka, Nobuhiro Fujikake, Katsuhito Ohno, Hiroyuki Higashiyama, Helena A. Popiel, Julia Rahadian, Masamitsu Yamaguchi, Warren J. Strittmatter, James R. Burke, and Tatsushi Toda. “Prevention of polyglutamine oligomerization and neurodegeneration by the peptide inhibitor QBP1 in Drosophila.Hum Mol Genet 12, no. 11 (June 1, 2003): 1253–59. https://doi.org/10.1093/hmg/ddg144.
Nagai Y, Fujikake N, Ohno K, Higashiyama H, Popiel HA, Rahadian J, et al. Prevention of polyglutamine oligomerization and neurodegeneration by the peptide inhibitor QBP1 in Drosophila. Hum Mol Genet. 2003 Jun 1;12(11):1253–9.
Nagai, Yoshitaka, et al. “Prevention of polyglutamine oligomerization and neurodegeneration by the peptide inhibitor QBP1 in Drosophila.Hum Mol Genet, vol. 12, no. 11, June 2003, pp. 1253–59. Pubmed, doi:10.1093/hmg/ddg144.
Nagai Y, Fujikake N, Ohno K, Higashiyama H, Popiel HA, Rahadian J, Yamaguchi M, Strittmatter WJ, Burke JR, Toda T. Prevention of polyglutamine oligomerization and neurodegeneration by the peptide inhibitor QBP1 in Drosophila. Hum Mol Genet. 2003 Jun 1;12(11):1253–1259.
Journal cover image

Published In

Hum Mol Genet

DOI

ISSN

0964-6906

Publication Date

June 1, 2003

Volume

12

Issue

11

Start / End Page

1253 / 1259

Location

England

Related Subject Headings

  • Promoter Regions, Genetic
  • Peptides
  • Oligopeptides
  • Neurodegenerative Diseases
  • Nervous System
  • Humans
  • Genetics & Heredity
  • Embryo, Nonmammalian
  • Drosophila
  • Disease Models, Animal