Protein misfolding and degradation in genetic diseases

Investigations of genetic diseases such as cystic fibrosis, alpha-1-antitry psin deficiency, phenylketonuria, mitochondrial acyl-CoA dehydrogenase defi ciencies, and many others have shown that enhanced proteolytic degradation of mutant proteins is a common molecular pathological mechanism. Detailed s tudies of the fate of mutant proteins in some of these diseases have reveal ed that impaired or aberrant folding of mutant polypeptides typically resul ts in prolonged interaction with molecular chaperones and degradation by in tracellular proteases before the functional conformation is acquired. This appears to be the case for many missense mutations and short in-frame delet ions or insertions that represent a major fraction of the mutations detecte d in genetic diseases. In some diseases, or under some circumstances, the d egradation system is not efficient. Instead, aberrant folding leads to accu mulation of protein aggregates that damage the cell. Mechanisms by which mi sfolded proteins are selected for degradation have first been delineated fo r the endoplasmatic reticulum; this process has been termed "protein qualit y control." Similar mechanisms appear to be operative in all cellular compa rtments in which proteins fold. Within the context of genetic diseases, we review knowledge on the molecular processes underlying protein quality cont rol in the various subcellular compartments, The important impact of such s ystems for variability of the expression of genetic deficiencies is emphasi sed. Hum Mutat 14:186-198, 1999. (C) 1999 Wiley-Liss, Inc.