Chemical and Biological Approaches Synergize to Ameliorate Protein-Folding Diseases

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2008.06.037 Byline: Ting-Wei Mu (1), Derrick Sek Tong Ong (1), Ya-Juan Wang (1)(2), William E. Balch (2)(3), John R. Yates (2), Laura Segatori (1), Jeffery W. Kelly (1) Keywords: PROTEINS; HUMDISEASE Abstract: Loss-of-function diseases are often caused by a mutation in a protein traversing the secretory pathway that compromises the normal balance between protein folding, trafficking, and degradation. We demonstrate that the innate cellular protein homeostasis, or proteostasis, capacity can be enhanced to fold mutated enzymes that would otherwise misfold and be degraded, using small molecule proteostasis regulators. Two proteostasis regulators are reported that alter the composition of the proteostasis network in the endoplasmic reticulum through the unfolded protein response, increasing the mutant folded protein concentration that can engage the trafficking machinery, restoring function to two nonhomologous mutant enzymes associated with distinct lysosomal storage diseases. Coapplication of a pharmacologic chaperone and a proteostasis regulator exhibits synergy because of the former's ability to further increase the concentration of trafficking-competent mutant folded enzymes. It may be possible to ameliorate loss-of-function diseases by using proteostasis regulators alone or in combination with a pharmacologic chaperone. Author Affiliation: (1) Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA (2) Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA (3) Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037, USA Article History: Received 17 July 2007; Revised 19 March 2008; Accepted 18 June 2008 Article Note: (miscellaneous) Published: September 4, 2008