Chemical Biology: Approaches to Drug Discovery and Development to Targeting Disease

Chapter 20: Protein Trafficking Diseases

Heidi M. Sampson

David Y. Thomas

McGill University, Quebec, Canada

Many diseases are caused by defects in protein trafficking. Protein trafficking diseases occur when a mutant protein is recognized by the endoplasmic reticulum (ER) quality control system (ERQC), retained in the ER, and degraded in the cytosol by the proteasome rather than being trafficked to its correct site of action. Among these diseases are cystic fibrosis, lysosomal storage diseases (Fabry, Gaucher, and Tay-Sachs), nephrogenic diabetes insipidus, oculocutaneous albinism, protein C deficiency, and many others. A characteristic of many of these diseases is that the mutant protein remains functional, but it cannot escape the stringent ER quality-control machinery, and it is retained in the ER. This characteristic suggests that pharmacological interventions that promote the correct folding of the mutant protein would enable its escape from the ER and ameliorate the symptoms of the disease. In this review, we focus on specific examples of protein trafficking diseases in pharmacological or chemical chaperones have been shown to rescue trafficking of the mutant protein.

The etiology of several diseases can be traced to defects in protein trafficking. Studies on several different disease mutants have shown that chemicals and small molecules can correct trafficking of these mutants. As these compounds promote correct folding in a fashion analogous to the action of molecular chaperone ...