Protein misfolding and disease
Protein homeostasis, or proteostasis, prevents the accumulation of misfolded or aggregated proteins. The EU-funded project PROTEOSTASIS (Cell-type-specific modulation of protein homeostasis in health and disease) has investigated if this essential machinery is cell-specific or more generic in nature, each cell being equipped with the molecular equipment to deal with a range of proteomes. The researchers used the free-living nematode worm Caenorhabditis elegans that has four bands of muscle cells running lengthways down the body, allowing movement. Using molecular tools and fluorescent reporters, they developed a strategy to delineate the chaperone network that keeps the folded proteins in the most stable state and fit for their normal biological functions. Responsible for temperature-dependent motility defects, mutations in the temperature sensitive (ts) unc-45 gene cause disorganised muscle filaments in the body wall under restrictive conditions but normal muscle filaments organization under permissive conditions. Using this behaviour, the researchers went on to identify four genes. Treatment with gene silencing interference RNA for the genes had no effect on the wild type worms, but had a profound disabling effect in the mutant worms already at the permissive temperature as compared with mutants grown at the restrictive temperature. Chaperones then may be specialised for a set of substrates to impact the folding function. PROTEOSTASIS results suggest that there is in part a cell-type specific set of chaperones that are adapted to the cell's needs. Further investigation of the capacity of proteostasis in different tissues under various physiological and stress conditions shows that there is a strong decline in folding capacity in the transition to adulthood. However, this can be regulated by the reproductive system and by germline stem cell arrest. Project results suggest that as proteostasis dysregulation is the main cause of age-related protein misfolding diseases, one fruitful research avenue would be understanding the nature of regulatory signals at transition to adulthood. This would give insight into how protein quality control systems are remodelled at that crucial stage.
