Protein transduction domain-mediated delivery of QBP1 suppresses polyglutamine-induced neurodegeneration in vivo

Mol Ther. 2007 Feb;15(2):303-9. doi: 10.1038/


Many neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and the polyglutamine (polyQ) diseases share common features including abnormal aggregation of misfolded proteins and their deposition as inclusion bodies in the brain. The polyQ diseases are caused by abnormal expansion of a polyQ stretch in each disease-causing protein, which triggers these proteins to form aggregates. We previously showed that genetic expression of the aggregate inhibitor peptide polyQ binding peptide 1 (QBP1) suppresses polyQ-induced neurodegeneration in Drosophila. However, to establish a molecular therapy using QBP1, QBP1 needs to be delivered into cells by its administration. In this study, we employed protein transduction domains (PTDs) to enable the efficient intracellular delivery of QBP1. We show here that fusion with a PTD enables the efficient intracellular delivery of QBP1, and that PTD-QBP1 treatment suppressed polyQ-induced cytotoxicity in cultured cells. Most importantly, oral administration of PTD-QBP1 successfully suppressed polyQ-induced premature death as well as polyQ inclusion body formation in a Drosophila model of the polyQ diseases, demonstrating its therapeutic effect against polyQ-induced neurodegeneration in vivo. Our study indicates that PTD-mediated delivery of aggregate inhibitor peptides is a promising therapeutic strategy for neurodegenerative diseases with abnormal aggregation of misfolded proteins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Animals, Genetically Modified
  • COS Cells
  • Chlorocebus aethiops
  • Disease Models, Animal
  • Drosophila / drug effects
  • Drosophila / genetics
  • Drosophila / metabolism
  • Inclusion Bodies / drug effects
  • Inclusion Bodies / metabolism
  • Macromolecular Substances / metabolism
  • Molecular Sequence Data
  • Nerve Degeneration / drug therapy*
  • Nerve Degeneration / genetics
  • Nerve Degeneration / metabolism
  • Oligopeptides / chemistry
  • Oligopeptides / metabolism
  • Oligopeptides / pharmacology*
  • Peptides / chemistry
  • Peptides / genetics
  • Peptides / metabolism*
  • Protein Binding


  • Macromolecular Substances
  • Oligopeptides
  • Peptides
  • polyglutamine-binding protein 1
  • polyglutamine