Inhibition of protein misfolding/aggregation using polyglutamine binding peptide QBP1 as a therapy for the polyglutamine diseases.

Journal Article (Journal Article;Review)

Protein misfolding and aggregation in the brain have been recognized to be crucial in the pathogenesis of various neurodegenerative diseases, including Alzheimer's, Parkinson's, and the polyglutamine (polyQ) diseases, which are collectively called the "protein misfolding diseases". In the polyQ diseases, an abnormally expanded polyQ stretch in the responsible proteins causes the proteins to misfold and aggregate, eventually resulting in neurodegeneration. Hypothesizing that polyQ protein misfolding and aggregation could be inhibited by molecules specifically binding to the expanded polyQ stretch, we identified polyQ binding peptide 1 (QBP1). We show that QBP1 does, indeed, inhibit misfolding and aggregation of the expanded polyQ protein in vitro. Furthermore overexpression of QBP1 by the crossing of transgenic animals inhibits neurodegeneration in Drosophila models of the polyQ diseases. We also introduce our attempts to deliver QBP1 into the brain by administration using viral vectors and protein transduction domains. Interestingly, recent data suggest that QBP1 can also inhibit the misfolding/aggregation of proteins responsible for other protein misfolding diseases, highlighting the potential of QBP1 as a general therapeutic molecule for a wide range of neurodegenerative diseases. We hope that in the near future, aggregation inhibitor-based drugs will be developed and bring relief to patients suffering from these currently intractable protein misfolding diseases.

Full Text

Duke Authors

Cited Authors

  • Popiel, HA; Takeuchi, T; Burke, JR; Strittmatter, WJ; Toda, T; Wada, K; Nagai, Y

Published Date

  • July 2013

Published In

Volume / Issue

  • 10 / 3

Start / End Page

  • 440 - 446

PubMed ID

  • 23504628

Pubmed Central ID

  • PMC3701761

Electronic International Standard Serial Number (EISSN)

  • 1878-7479

Digital Object Identifier (DOI)

  • 10.1007/s13311-013-0184-7


  • eng

Conference Location

  • United States