Cellular pathophysiology of conformational disorders

Protein aggregation is a hallmark of a growing group of pathologies known as conformational diseases. Their most intensively studied examples include Alzheimer's disease, Parkinson's disease, Huntington's disease and spongiform encephalopathies (prion diseases). Numerous studies have indicated that different polypeptides use common cellular mechanisms to form aggregates. As a consequence, many unrelated proteins accumulate in similar aggregation-related structures, with extracellular amyloid fibrils and intracellular aggresomes being the best known examples. On the other hand, certain features of the aggregation process seem to be specific to particular proteins or even to particular amino acid sequences. Several different mechanisms have been so far proposed to explain the relationship between the abnormal aggre-gation of misfolded proteins and the pathophysiology of particular conformational diseases. For example, the aggregates have been assumed to form abnormal structures within neurites that block the intracellular transport between the cell body and the cellular periphery, thus obstructing the delivery of crucial cellular factors to the syn-apses. Another model of cellular pathophysiology points to the ability of the aggregation intermediates, namely small hydrophobic protein oligomers, to form non-specific channels within the cellular membranes, especially within the mitochondrial membrane, which could potentially contribute to the mitochondrial dysfunction and subsequent cell death. However, during the last decade most attention has been given to the so-called sequestra-tion hypothesis, that connects abnormal protein aggrega-tion with increased sequestration of crucial cellular proteins. Although it is not clear whether the aggregation of misfolded proteins is a primary cause or merely a consequence of disease, many therapeutic strategies are directed towards reducing the aggregation level of the disease-causing protein. The most promising approaches include (1) the development of specific antibodies or small peptides that bind the aggregating proteins and reduce their aggregation level, (2) using molecular chaperones to increase the efficiency of proper protein folding, and thus reduce the aggregation rate, and finally (3) the development of the RNAi-based therapy, aimed at silencing the genes encoding the aggregating proteins. The chaperone protein network controls both initial protein folding and subsequent maintenance of proteins in the cell. Although the native structure of a protein is principally encoded in its amino acid sequence, the process of folding in vivo very often requires the assistance of molecular chaperones. Chaperones also play a role in a post-translational quality control system and thus are required to maintain the proper conformation of proteins under changing environmental conditions. The disruption of protein folding quality control …