earticle

영어

Formation of non-native protein conformers is inherent to the process of de novo protein synthesis. Non-native protein conformations are recognized as being not correctly folded and retained by the cellular quality control of protein folding to become eventually degraded, mainly by the ubiquitin-proteasome system. Under various forms of cellular stress and due to mutations, a surplus of misfolded glycoproteins in the endoplasmic reticulum (ER) results in
ER stress. Such ER stress is commonly associated with a large spectrum of human disorders caused by protein misfolding and results in the up-regulation of the unfolded protein response (UPR). Up-regulation of UPR has severe general consequences for cells and organs and eventually leads to inflammation and apoptotic cell death. Depending on the type of the protein affected, its misfolding can result in a loss-of-function or in a pathological-gain-of-function
protein folding disorder (Roth, 2002; Roth et al., 2008). Attempts have been made to rescue the folding defect in various human protein folding disorders by synthetic chaperones. Different types of synthetic chaperones have been tested for therapeutic purposes: pharmacological chaperones such as ligand analogues and competitive enzyme inhibitors, and synthetic chaperones such as glycerol, DMSO and 4-phenylbutyrate. Two specific examples will be discussed to demonstrate the potential of synthetic chaperones: (i) use of 1-deoxygalactonojirimycin, a competitive inhibitor of alpha-galactosidase A, the protein affected in Fabry disease (Yam et al. 2005, 2006), and (ii) the use of 4-phenylbutyrate in myocilin-caused open-angle glaucoma (Yam et al. 2007 a-c).