Theme 2

From the expertise in Biosciences theme 2 aims to determine how cells respond to protein aggregation and to identify cell engineering strategies that may be used to evade the problems protein misfolding presents. All eukaryotic cells contain a finely balanced quality control system to ensure their newly synthesised proteins are correctly folded. At the heart of this QC system lies an effectively co-ordinated and optimised protein chaperone network. When protein misfolding occurs, these errors are usually effectively reversed where possible through this network. Alternatively, the misfolded protein is disposed of via the ubiquitin-proteasome pathway. Critically, protein misfolding often triggers protein aggregation that not only leads to a ‘loss-of-function’ of the aggregated protein but also a gain-of-function’ through the formation of toxic oligomeric species formed through an ‘off-pathway’ step. It can also impact on ‘protein homeostasis’ by triggering other proteins to misfold. Protein aggregation undoubtedly has a major impact on the fitness of a cultured eukaryotic cell or can lead to disease at the organismal level.  This theme will focus upon the following scientific aspects:

(a) Design and exploitation of cellular systems for optimum and authentic protein folding. Crucial to the exploitation of eukaryotic expression systems, which in our case will be CHO and yeast (Pichia and Saccharomyces), is the prevention of unwanted protein aggregation. Failure to correctly fold a native or recombinant protein will result in a loss of productivity as well as authenticity. Our strategy will be to define the components of the chaperone network that deals specifically with protein aggregates and to engineer cells to ensure such activities are able to deal effectively with cytoplasmic and secreted recombinant proteins.

(b) Development and exploitation of non-animal models of protein misfolding diseases. A series of yeast strains and cultured cell lines expressing a range of different proteins whose misfolding has been implicated in human disease, will be developed. They will be exploited both to facilitate a further understanding of the cellular responses to protein misfolding but will also provide a novel screening platform for drugs that prevent the formation of toxic, disease-associated oligomers. Early targets will be Alzheimer’s disease (A) and Amyotrophic Lateral Sclerosis (ALS; superoxide dismutase).