title: Chemical and biological approaches synergize to ameliorate protein-folding diseases.
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.
authors.affiliation: Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Ting-Wei
authors.initials: TW
authors.lastname: Mu
authors.forename: Derrick Sek Tong
authors.initials: DS
authors.lastname: Ong
authors.forename: Ya-Juan
authors.initials: YJ
authors.lastname: Wang
authors.forename: William E
authors.initials: WE
authors.lastname: Balch
authors.forename: John R
authors.initials: JR
authors.lastname: Yates
authors.forename: Laura
authors.initials: L
authors.lastname: Segatori
authors.forename: Jeffery W
authors.initials: JW
authors.lastname: Kelly
mesh_terms: D002460:Cell Line; D005347:Fibroblasts / Q000378:metabolism; D005776:Gaucher Disease / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D016464:Lysosomal Storage Diseases / Q000188:drug therapy / Q000378:metabolism*; D018832:Molecular Chaperones / Q000494:pharmacology; D053978:Pentacyclic Triterpenes; D017510:Protein Folding; D011506:Proteins / Q000378:metabolism*; D013661:Tay-Sachs Disease / Q000188:drug therapy / Q000378:metabolism; D014315:Triterpenes / Q000494:pharmacology
chemical_list: D007976:Leupeptins; D018832:Molecular Chaperones; D053978:Pentacyclic Triterpenes; D011506:Proteins; D014315:Triterpenes; C050414:celastrol; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde
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