New Cell-Death Pathway Found

Disease-related misfolded proteins trigger a previously unknown apoptotic pathway, researchers report (Nat. Chem. Biol., DOI: 10.1038/nchembio.467). Using a cell-based model of Huntington’s disease, Brent R. Stockwell and coworkers at Columbia University identified five small molecules that inhibit protein disulfide isomerase (PDI) and thereby suppress cell apoptosis induced by mutant huntingtin protein. The researchers tested three of the compounds (one shown) in rat brain slices exposed to the protein; adding the inhibitors protected neurons from apoptosis. The same molecules protected rat neurons from cell death triggered by the Aβ peptide, which is associated with Alzheimer’s disease. “This work is highly significant because it squarely places a known protein, PDI, at the center of the integration point between misfolded proteins and the triggering of an apoptotic death pathway,” says Guy Salvesen, an apoptosis expert at the Sanford-Burnham Medical Research Institute, in La Jolla, Calif. “This novel connection provides a pleasing answer to the vexing question of how misfolded proteins induce apoptosis and also a potential therapeutic control point that can be leveraged pharmaceutically.”