PERSPECTIVES Clearing Conformational Disease MEDICINE

Toxicity caused by aggregates of a misfolded protein is abolished with a drug that boosts cellular protein degradation mechanisms. R esearch focused on defining the underlying characteristics of a dis-ease can often lead to new treatment strategies. This is certainly the case for a rap-idly expanding group of inherited diseases characterized by the toxic accumulation of a misfolded protein ( 1). Identifying, and then targeting, the cellular machinery responsi-ble for orchestrating the degradation of these aberrant molecules, rather than correcting the mutations that cause them, represents a par-adigm shift from the conventional wisdom associated with gene therapy. On page 229 of this issue, Hidvegi et al. ( 2) describe how a compound that stimulates autophagy— the process by which a cell destroys its own organelles through lysosomal compart-ments—can successfully eliminate the toxic effects of misfolded α 1-antitrypsin protein in a preclinical mouse model of the associated liver disease ( 3). α 1-Antitrypsin, which is primarily syn-thesized in the liver (hepatocytes), is inserted into the endoplasmic reticulum (ER), where only the correctly folded monomer is allowed to travel as a soluble itinerant protein through an intracellular secretory pathway, for even-tual release at the cell surface. A surveillance system initially assists the molecule’s folding. Correct folding of α 1-antitrypsin involves modifi cation of sugar moieties attached to specifi c asparagine residues ( 4, 5). Thereaf-ter, ER-associated degradation (ERAD) pro-cesses proteolyze and eliminate those mole-cules unable to achieve the correct structure ( 6). Misfolded monomers are extracted into the cytoplasm for elimination by 26S protea-somes ( 7). By retaining misfolded proteins and targeting them for destruction, the cir-culating concentration of α 1-antitrypsin is consequently low. This decrease in secrete