The unfolded protein response in protein aggregating diseases

For many genetic diseases, clinical phenotypes arise through the dysfunction of the gene products encoded by mutant genes. Effective treatment entails providing a source of the gene product in the diet or circulation, as has been achieved for type 1 diabetes and hemophilia, or in cases of enzyme deficiency by supplementation with metabolites synthesized by the defective protein, as in adrenoleukodystrophy. However, a growing list of diseases do not appear to be amenable to such treatment strategies. In these instances, defective gene products acquire novel properties that disrupt normal cell function, even in the presence of proteins encoded by the normal allele. One class of such diseases, collectively termed conformational diseases, is composed of clinically unrelated disorders that share a common pathophysiology because the mutant proteins cannot adopt stable three-dimensional conformations. These mutant proteins aggregate in various subcellular compartments and may even cause cell death. Some of these diseases are associated with inclusion bodies containing the aggregating proteins whereas others do not exhibit such pathology; however, all appear to activate cell stress signaling pathways. Herein, we highlight one such disorder, Pelizaeus-Merzbacher disease, that disrupts formation of whiter matter in the brain. Accumulation of the mutant protein in oligodendrocytes activates the unfolded protein response. The well-characterized genetics and large number of animal models available for Pelizaeus-Merzbacher disease enables this disease to serve as an important model for conformational diseases, both in terms of defining molecular components of the unfolded protein response signaling pathway as well as testing therapeutic approaches to ameliorate disease.