Hsp40 gene therapy exerts therapeutic effects on polyglutamine disease mice via a non-cell autonomous mechanism

PLoS One. 2012;7(11):e51069. doi: 10.1371/journal.pone.0051069. Epub 2012 Nov 30.


The polyglutamine (polyQ) diseases such as Huntington's disease (HD), are neurodegenerative diseases caused by proteins with an expanded polyQ stretch, which misfold and aggregate, and eventually accumulate as inclusion bodies within neurons. Molecules that inhibit polyQ protein misfolding/aggregation, such as Polyglutamine Binding Peptide 1 (QBP1) and molecular chaperones, have been shown to exert therapeutic effects in vivo by crossing of transgenic animals. Towards developing a therapy using these aggregation inhibitors, we here investigated the effect of viral vector-mediated gene therapy using QBP1 and molecular chaperones on polyQ disease model mice. We found that injection of adeno-associated virus type 5 (AAV5) expressing QBP1 or Hsp40 into the striatum both dramatically suppresses inclusion body formation in the HD mouse R6/2. AAV5-Hsp40 injection also ameliorated the motor impairment and extended the lifespan of R6/2 mice. Unexpectedly, we found even in virus non-infected cells that AAV5-Hsp40 appreciably suppresses inclusion body formation, suggesting a non-cell autonomous therapeutic effect. We further show that Hsp40 inhibits secretion of the polyQ protein from cultured cells, implying that it inhibits the recently suggested cell-cell transmission of the polyQ protein. Our results demonstrate for the first time the therapeutic effect of Hsp40 gene therapy on the neurological phenotypes of polyQ disease mice.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / pathology
  • Brain / physiopathology
  • Cells, Cultured
  • Dependovirus / metabolism
  • Disease Models, Animal
  • Genetic Therapy*
  • HSP40 Heat-Shock Proteins / genetics*
  • HSP40 Heat-Shock Proteins / therapeutic use*
  • Hand Strength / physiology
  • Huntington Disease / genetics*
  • Huntington Disease / pathology
  • Huntington Disease / physiopathology
  • Huntington Disease / therapy*
  • Inclusion Bodies / metabolism
  • Longevity
  • Mice
  • Motor Activity / physiology
  • Neurons / metabolism
  • Neurons / pathology
  • Neurons / virology
  • Oligopeptides / genetics
  • Oligopeptides / therapeutic use
  • Peptides / metabolism*
  • Phenotype
  • Weight Loss


  • HSP40 Heat-Shock Proteins
  • Oligopeptides
  • Peptides
  • polyglutamine-binding protein 1
  • polyglutamine

Grant support

This work was supported in part by Grants-in-Aid for Scientific Research on Priority Areas (Research on Pathomechanisms of Brain Disorders and Protein Community to Y.N.), and on Innovative Areas (Synapse and Neurocircuit Pathology to Y.N. and S.M.) and by a Comprehensive Brain Science Network Award for Young Scientists to H.A.P., from the Ministry of Education, Culture, Sports, Science, and Technology, Japan; by Grants-in-Aid for Scientific Research (B) to Y.N., for Young Scientists (B) to H.A.P., from the Japan Society for the Promotion of Science, Japan; by a Grant-in-Aid for the Research Committee for Ataxic Diseases to Y.N. and a Grant-in-Aid for the Research Committee of CNS Degenerative Diseases to S.M. from the Ministry of Health, Labor and Welfare, Japan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.