Therapy through chaperones: sense or antisense? Cystic fibrosis as a model disease

J Inherit Metab Dis. 2006 Apr-Jun;29(2-3):477-87. doi: 10.1007/s10545-006-0251-x.


Massive production and accumulation of a single abnormal protein may constitute a major toxic burden for the cell and even compromise the organism's long-term viability. Consequently, adaptation and survival have forced evolution to create 'quality control' mechanisms that detect, monitor, and often degrade such abnormally folded gene products, in which molecular chaperones are key players. Notwithstanding this, there are numerous examples of misfolded proteins which, in spite of being recognized as aberrant and efficiently discarded by cellular quality control, still retain some of the functional properties of their wild-type counterparts, so that their maintenance in the cell would be beneficial for the organism. Herein are described the cellular roles of molecular chaperones and some new insights on the mechanisms by which they influence the development of human diseases caused by mutations that lead to protein misfolding. A special emphasis is given to cystic fibrosis, a classical genetic disorder resulting from the retention and degradation of a mutant, albeit functional, protein by the endoplasmic reticulum quality control. This particular system has been a good example to describe the mechanisms that are likely to be shared by a number of protein substrates, to define the common characteristics of the mutants, as well as to identify the mechanistic intervenients in their retention and degradation. Finally, new approaches aimed at correcting protein folding defects are discussed, including the potential of molecular chaperones (e.g., through RNA interference) as novel therapeutic targets, and the usage of chemical or pharmacological chaperones as new therapeutic agents.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Cystic Fibrosis / genetics
  • Cystic Fibrosis / metabolism*
  • Cystic Fibrosis / therapy*
  • Cystic Fibrosis Transmembrane Conductance Regulator / drug effects
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics
  • Cystic Fibrosis Transmembrane Conductance Regulator / metabolism*
  • Humans
  • Molecular Chaperones / metabolism*
  • Molecular Chaperones / pharmacology
  • Mutation
  • Protein Conformation
  • Protein Folding


  • Molecular Chaperones
  • Cystic Fibrosis Transmembrane Conductance Regulator