Osmolytes are naturally occurring small organic molecules present in all kingdoms of life. These organic molecules are accumulated by living systems to circumvent stress conditions. A number of human diseases have been grouped under the protein-misfolding diseases. These entire diseases share the same hallmarks of the presence of cellular inclusions and plaques that are deposited in the cells and tissues affected by the disease. These misfolded forms of protein are responsible for initiating toxic cascades in the cell, causing vesicle dystrafficking, synaptic and cell organelle dysfunction, and ultimately cell death. Published results suggest that cells regulate many biological processes such as protein folding, protein disaggregation, and protein-protein interactions via accumulation of specific osmolytes. Since, as of now, complete cure for these protein-misfolding disorders does not exist; therefore, it becomes increasingly important to review the recent works on this aspect to develop strategies for therapeutics. It has been shown that certain osmolytes can prevent the proteins from misfolding. Thus, osmolytes can be utilized as therapeutics for such diseases. In this review article, we discuss the role of naturally occurring osmolytes in various forms of amyloidosis associated with human diseases.
Intracellular Organic Osmolytes: Function and Regulation (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2276334/):
The basic concepts, as described then and still valid, are as follows. 1) All water-stressed organisms, except halobacteria, accumulate intracellular organic osmolytes in response to water stress. 2) The major systems of organic osmolytes include polyhydric alcohols, free amino acids and their derivatives, and combinations of urea and methylamines. 3) The evolutionary advantage of the organic osmolyte systems is compatibility with macromolecular structure and function at high and variable osmolyte concentrations without modifying cellular proteins to function in concentrated intracellular solutions. 4) Osmolyte compatibility results from non-perturbing or favorable effects of osmolytes on macromolecule-solvent interactions.
The osmolality of mammalian blood is normally kept remarkably constant at ∼290 mosmol/kg by a combination of thirst and varying urinary concentrations. Therefore, most mammalian cells are not normally exposed to the extreme osmolalities experienced by the cells discussed above. Nevertheless, certain mammalian cells contain considerable concentrations of organic osmolytes, and most of the rest are able to accumulate them if suitably stressed. Renal medullary cells contain the highest levels of organic osmolytes consequent to their being exposed to extremely high concentrations of NaCl and urea because of their roles in concentrating the urine. The principal organic osmolytes in renal medullary cells are sorbitol, betaine, inositol, taurine, and glycerophosphocholine (GPC). Cells in other tissues may also experience hyperosmolality, albeit to a lesser degree than in the renal medulla. Accordingly, they also accumulate organic osmolytes. The principal ones in brain are amino acids, choline, creatine, inositol, and taurine (20). Liver cells accumulate betaine, inositol, and taurine (21).
TonEBP/OREBP (also named NFAT5) is the transcription factor that mediates hypertonicity-induced transcription of AR, BGT1, SMIT, tauT, and NTE (2).