Implications of ageing and disease on cellular protein quality control
Cellular proteostasis is the intricate, finely tuned balance of protein synthesis, maintenance, and degradation, essential for sustaining cellular health and linked to longevity. It continually faces challenges from unfolded proteins produced during biosynthesis, misfolding due to genetic errors, and damage caused by proteotoxic stressors. Chaperones and other protein quality control (PQC) factors are in place to facilitate proper protein folding and prevent the accumulation of abnormal misfolded proteins. While PQC systems typically maintain proteome integrity under normal conditions, aging reduces this capacity, contributing to various human diseases, including cancer and neurodegenerative disorders. Accumulating intracellular damage is a hallmark of aging, as the proteostasis network becomes burdened with increasing loads of misfolded and oxidatively damaged proteins. The decline in maintaining a functional proteome is a key driver of age-related cellular dysfunction and degenerative diseases.
With our research, we will enter novel grounds by studying the interplay of localized PQC systems and their change over different life stages and conditions, thus adding age and age-related disorders as additional complexity factor. Our research is based at the intersection point between data- and hypothesis-driven research, implementing powerful bioinformatic analyses to understand new aspects of PQC as one of the most fundamental processes of cellular life. We will combine the simplicity of yeast with the multifacetedness of human cell culture. Yeast's unique attributes, such as its remarkable adaptability, exceptionally short lifespan, and high interspecies conservation, render it an excellent model for investigating aging and proteostasis. Furthermore, the availability of multiple whole-genome libraries, which enable the straightforward identification of individual mutants through unique barcodes, enhances its suitability for high-throughput experiments. Our ultimate aim is to translate knowledge acquired from yeast research into a deeper understanding of the aging processes in human cells. Yeast acts as a valuable roadmap, helping us identify the critical pathways to explore, which we can then investigate within the intricate landscape of human cell culture.