Protein misfolding disorders: pathogenesis and intervention.

Newly synthesized proteins in the living cell must go through a folding process to attain their functional structure. To achieve this in an efficient fashion, all organisms, including humans, have evolved a large set of molecular chaperones that assist the folding as well as the maintenance of the functional structure of cellular proteins. Aberrant proteins, the result of production errors, inherited or acquired amino acid substitutions or damage, especially oxidative modifications, can in many cases not fold correctly and will be trapped in misfolded conformations. To rid the cell of misfolded proteins, the living cell contains a large number of intracellular proteases, e.g. the proteasome, which together with the chaperones comprise the cellular protein quality control systems. Many inherited disorders due to amino acid substitutions exhibit loss-of-function pathogenesis because the aberrant protein is eliminated by one of the protein quality control systems. Examples are cystic fibrosis and phenylketonuria. However, not all aberrant proteins can be eliminated and the misfolded protein may accumulate and form toxic oligomeric and/or aggregated inclusions. In this case the loss of function may be accompanied by a gain-of-function pathogenesis, which in many cases determines the pathological and clinical features. Examples are Parkinson and Huntington diseases. Although a number of strategies have been tried to decrease the amounts of accumulated and aggregated proteins, a likely future strategy seems to be the use of chemical or pharmacological chaperones with specific effects on the misfolded protein in question. Positive examples are enzyme enhancement in a number of lysosomal disorders.