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Chemical and biological approaches synergize to ameliorate protein-folding diseases

Academic Article
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Overview

related to degree

  • Ong, Derrick, Ph.D. in Chemical Biology, Scripps Research 2007 - 2011

authors

  • Mu, T. W.
  • Ong, Derrick
  • Wang, Y. J.
  • Balch, William E.
  • Yates III, John
  • Segatori, L.
  • Kelly, Jeffery

publication date

  • September 2008

journal

  • Cell  Journal

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.

subject areas

  • Cell Line
  • Fibroblasts
  • Gaucher Disease
  • Humans
  • Leupeptins
  • Lysosomal Storage Diseases
  • Molecular Chaperones
  • Protein Folding
  • Proteins
  • Tay-Sachs Disease
  • Triterpenes
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Identity

PubMed Central ID

  • PMC2650088

International Standard Serial Number (ISSN)

  • 0092-8674

Digital Object Identifier (DOI)

  • 10.1016/j.cell.2008.06.037

PubMed ID

  • 18775310
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Additional Document Info

start page

  • 769

end page

  • 781

volume

  • 134

issue

  • 5

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