Definitely since the beginning of the year, we have seen important publications in the neurodegenerative field. This concerns a fundamental aspect of research, rather than a clinical aspect.
Many age-related diseases, including Alzheimer's and Parkinson's, are caused by the aggregation of misfolded proteins that seem to be parked in the cytosol, instead of being shipped to where they should operate. The mechanisms underlying how aging causes protein aggregation are largely unknown.
Since protein synthesis is energetically expensive, the ribosome must balance the costs of efficiently manufacturing a protein with those of correctly folding it. When correctly folded, proteins perform their functions and remain soluble in the environment of the cell. However, larger proteins naturally have greater conformational variety, so the folding of these proteins requires tight control to ensure that the folding does not occur in one of multiple unproductive or misfolded pathways. cannot work properly and tend to stick to each other and other proteins, obstructing cellular processes and forming toxic aggregates.
Researchers at Stanford University have particularly studied the functioning of ribosomes and the influence of their dysfunction on the production of misfolded proteins.
In fact, the outer (cytosolic) face of the rough endoplasmic reticulum is dotted with ribosomes, but they are also found throughout the cytoplasm.
The role of the ribosome is to make new proteins. It does this by moving along a strand of messenger RNA and building a protein based on the code it reads. Making a protein this way is called translation. There are up to 10 million ribosomes in each cell.
Generating a functional proteome requires the ribosome to carefully regulate the disparate co-translational processes that determine the fate of nascent polypeptides. The non-uniform rate of translation elongation that defines translation kinetics appears to be the primary means of regulating this trade-off.
In new research published Jan. 19 in Nature, these researchers attributed this problem to a deficiency in the ribosomal machinery, which deficiency is age-related. Researchers in the lab of Judith Frydman, Donald Kennedy Professor of the Stanford School of Humanities, used two well-established models of human aging, yeast and roundworms. Aging modifies the elongation kinetics of translation in Caenorhabditis elegans and Saccharomyces cerevisiae.
Ribosome pausing was exacerbated at specific positions in yeast and aged worms, including polybasic stretch, resulting in increased ribosome collisions known to trigger ribosome-associated quality control (RQC). Notably, aged yeast cells exhibited impaired clearance and increased aggregation of RQC substrates.
Very small changes in folding efficiency with age will intensify in a vicious circle where translational defects lead to system overload, which in turn leads to increased protein aggregates with age which are themselves also toxic.