Stress and molecular chaperones in disease.

Stress, a common phenomenon in today's society, is suspected of playing a role in the development of disease. Stressors of various types, psychological, physical, and biological, abound. They occur in the working and social environments, in air, soil, water, food, and medicines. Stressors impact on cells directly or indirectly, cause protein denaturation, and elicit a stress response. This is mediated by stress (heat-shock) genes and proteins, among which are those named molecular chaperones because they assist other proteins to achieve and maintain a functional shape (the native configuration), and to recover it when partially lost due to stress. Denatured proteins tend to aggregate and precipitate. The same occurs with abnormal proteins due to mutations, or to failure of post-transcriptional or post-translational mechanisms. These abnormal proteins need the help of molecular chaperones as much as denatured molecules do, especially during stress. A cell with normal antistress mechanisms, including a complete and functional set of chaperones, may be able to withstand stress if its intensity is not beyond that which will cause irreversible protein damage. There is a certain threshold that normal cells have above which they cannot cope with stress. A cell with an abnormal protein that has an intrinsic tendency to misfold and aggregate is more vulnerable to stress than normal counterparts. Furthermore, these abnormal proteins may precipitate even in the absence of stress and cause diseases named proteinopathies. It is possible that stress contributes to the pathogenesis of proteinopathies by promoting protein aggregation, even in cells that possess a normal chaperoning system. Examples of proteinopathies are age-related degenerative disorders with protein deposits in various tissues, most importantly in the brain where the deposits are associated with neuronal degeneration. It is conceivable that stress enhances the progression of these diseases by facilitating protein unfolding and misfolding, which lead to aggregation and deposition. A number of reports in the last few years have described research aimed at elucidating the role of heatshock proteins, molecular chaperones in particular, in the pathogenesis of neurodegenerative disorders. The findings begin to shed light on the molecular mechanism of protein aggregation and deposition, and of the ensuing cell death. The results also begin to elucidate the role of molecular chaperones in pathogenesis. This is a fascinating area of research with great clinical implications. Although there are already several experimental models for the study of proteinopathies, others should be developed using organisms that are better known now than only a few years ago and that offer unique advantages. Use of these systems and of information available in databases from genome sequencing efforts should boost research in this field. It should be possible in the not-too-distant future to develop therapeutic and preventive means for proteinopathies based on the use of heat-shock protein and molecular chaperone genes and proteins.