Folding Proteins

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Science  12 Sep 2008:
Vol. 321, Issue 5895, pp. 1419
DOI: 10.1126/science.321.5895.1419b

In many patients who suffer from loss-of-function genetic diseases, the missing protein is translated, but a point mutation causes misfolding and subsequent degradation of the protein. Pharmacologic chaperones, which help to restore function by binding to and stabilizing successfully folded proteins, have shown some therapeutic promise, but are inherently disease-specific. A more general strategy to encourage proper folding would be to enhance cellular protein homeostasis mechanisms, including the unfolded protein response (UPR) and the heat-shock response (HSR). Mu et al. have identified two small molecules, celastrol and the proteasome inhibitor MG-132, that each increase mutant protein folding and activity in patient-derived cell lines from two different lysosomal storage diseases, Gaucher and Tay-Sachs. These compounds up-regulate multiple UPR and HSR components, and two UPR proteins of the endoplasmic reticulum (IRE1 and PERK) are required to mediate the beneficial effects in both cell lines. Coapplication of these drugs with known pharmacological chaperones had a synergistic effect and increased the activity of the mutant proteins to at least 50% of wild-type activity. These results provide a proof-of-principle milestone in the therapeutic approach of developing protein homeostasis regulators to treat a range of loss-of-function diseases. — NM*

cell 134, 10.1016/j.cell.2008.06.037 (2008).

  • * Nilah Monnier is a summer intern in Science's editorial department.

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