Inhibition of RNA Quality Control in Differentiating and Aging Cells

2013 new Scholar Award in aging

The accumulation of misfolded proteins contributes to many diseases, ranging from disorders of the eye to neurodegeneration. These protein misfolding and aggregation diseases are strongly associated with aging, suggesting that older cells are unable to effectively clear damaged proteins. Accordingly, much research has focused on understanding how aging reduces normal protein quality control. Recently, we and others found that other cellular quality control mechanisms become less efficient during aging as well, potentially contributing to aging-associated disorders. Proteins are encoded by messenger RNAs, which undergo alternative splicing to generate proteome diversity. As alternative splicing is a noisy and error-prone process, it is important for the cell to be able to recognize and degrade incorrectly spliced mRNAs. We found that the major mRNA quality control pathway, nonsense-mediated decay, becomes less efficient as cells age. This suggests that aging-associated increases in protein misfolding and aggregation may be due to reductions in the efficiency of both RNA and protein quality control. The goal of our research is to understand why mRNA quality control efficiency decreases with age, in order to determine how this reduced efficiency may contribute to aging-associated protein aggregation disorders.

Robert K. Bradley Ph.D.
Fred Hutchinson Cancer Research Center