Stress and molecular chaperones in disease

Stress, a common phenomenon in today's society, is suspected of playing a r ole in the development of disease. Stressors of various types, psychologica l, physical, and biological, abound. They occur in the working and social e nvironments, in air, soil, water, food, and medicines. Stressors impact on cells directly or indirectly, cause protein denaturation, and elicit a stre ss response. This is mediated by stress (heat-shock) genes and proteins, am ong which are those named molecular chaperones because they assist other pr oteins 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 d ue to mutations, or to failure of post-transcriptional or post-translationa l mechanisms. These abnormal proteins need the help of molecular chaperones as much as denatured molecules do, especially during stress. A cell with n ormal antistress mechanisms, including a complete and functional set of cha perones, may be able to withstand stress if its intensity is not beyond tha t which will cause irreversible protein damage. There is a certain threshol d that normal cells have above which they cannot cope with stress. A cell w ith an abnormal protein that has an intrinsic tendency to misfold and aggre gate is mon vulnerable to stress than normal counterparts. Furthermore, the se abnormal proteins may precipitate even in the absence of stress and caus e 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 proteinopat hies are age-related degenerative disorders with protein deposits in variou s tissues, most importantly in the brain where the deposits are associated with neuronal degeneration. It is conceivable that stress enhances the prog ression 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 heat-sho ck proteins, molecular chaperones in particular, in the pathogenesis of neu rodegenerative disorders. The findings begin to shed light on the molecular mechanism of protein aggregation and deposition, and of the ensuing cell d eath. 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 t he study of proteinopathies, others should be developed using organisms tha t are better known now than only a few years ago and that offer unique adva ntages. Use of these systems and of information available in databases from genome sequencing efforts should boost research in this field. It should b e possible in the not-too-distant future to develop therapeutic and prevent ive means for proteinopathies based on the use of heat-shock protein and mo lecular chaperone genes and proteins.