Role of quality control pathways in human diseases involving protein misfolding

Advances in connecting phenotype to genotype have led to new insights regarding the basis of human disease. Many inherited diseases are now known to arise due to specific mutations within a gene that then lead to a protein product unable to assume a stable conformation within the cell. Cellular machineries serving as "quality control monitors" recognize and target such abnormally folded proteins for rapid destruction. As a consequence, specific biochemical pathways requiring the protein of interest are adversely affected and lead to the disease phenotype. Yet in other cases, upon its misfolding the particular protein quickly aggregates, leading to the formation of inclusion bodies that eventually lead to cell demise. In what follows I discuss some classic examples of human diseases known to arise due to mutations that lead to altered protein folding, abnormal protein maturation and/or protein aggregation. In many cases simply altering the protein folding environment within the cell, via molecular or pharmacological approaches, can effectively rescue the maturation and stability of the mutant protein and thereby reduce the onset and/or progression of the disease phenotype. These new insights regarding the mechanisms underlying the disease phenotype, as well as new approaches to correct the protein folding defect, will undoubtedly prove to have a tremendous impact on clinical medicine. (C) 2003 Elsevier Ltd. All rights reserved.