Different degenerative diseases of the central nervous system (CNS) appear after middle age, and increase in frequency in the elderly. They seem to be associated with aging. Data suggest that while aging is partly dictated by genetic determinants, environmental stressors also play a role. Normal aging and a decrease in the capacity to mount a stress response go in parallel. Conversely, genetic conditions that confer longevity are accompanied by improved capacity to respond to stressors. Stress proteins and molecular chaperones are the typical manifestations of the stress response. They play a key role in peptide folding and trafficking, and thus maintain the normal cellular set of protein molecules in their native (functional) configuration. This set of proteins enables the cell to function and to survive stressful situations. Due to gene mutations, defective peptides may appear that have a tendency to misfold and form deposits in vital tissues, e.g., those of the CNS, a condition that is usually associated with degenerative diseases. It remains to be determined how much stress proteins and molecular chaperones participate in the aging process, and in the pathogenesis of the degenerative diseases accompanying this process in many individuals. Because of the known role of chaperones in maintaining the normal set of proteins in a functional configuration, one might assume that chaperones are key players in pathogenesis. Chaperones may prevent protein misfolding, and aggregation, and may mediate dissolution of protein deposits. Likewise, chaperones may become trapped in protein aggregates when they bind defective peptides but cannot assist in their correct folding, or cannot release them, owing to a defect in the pathologic peptide. This entrapment is suggested by the presence of chaperones in pathologic protein deposits. The cell's protein balance also depends on degradation. One might say that the normal set of proteins in a cell is maintained by generation of new molecules and, at the other end of the pathway, by proteolysis. Old, damaged, proteins are eliminated by proteolytic systems, and the same may happen to defective peptides due to gene mutations if they cannot be driven by chaperones into the functional pool. Arguably, molecular chaperones are in the central, most critical, portion of the protein assembly line. They play a crucial role as they assist in the correct folding of new peptides, or present those destined for degradation to proteases. Protein deposits in degenerative diseases may be due not only to a failure of the folding mechanism, but also to a failure of the proteolytic system. Participation of the latter is evidenced by the presence of some of its components (e.g., ubiquitin) in the pathologic protein deposits. Future research aiming at elucidating the role of chaperones in degenerative diseases, whether as pathogenetic factors or preventive-curative tools, ought to explore a number of possibilities. For example, folding of mutant peptides ought to be assessed in vivo and in vitro. One will have to take into account that chaperones function as complex machines and interact with other molecules and structures. Information from comparative analyses of gene, protein, and genome sequences should help in the selection of experimental systems and molecular targets for investigation. The effect of stressors with which humans are confronted daily, ought to be measured to assess their role on peptide misfolding and aggregation, and in disease onset and progression in individuals genetically susceptible to degenerative diseases. One might argue that the presence of a defective peptide requires the chaperone system constantly. When a stressor hits the cell, the chaperone system is partly diverted to protect and rescue normal peptides damaged by stress and must abandon some copies of the defective peptide. These "unprotected" copies misfold and precipitate. Stress would thus play a critical role in disease onset and progression by creating a functional overload to the chaperone system, already overextended because of the presence of the mutant peptide. © 2001.
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