Major Focus Area
My group identified clusterin (CLU) as the first known extracellular mammalian chaperone (EC) and since then I have authored more than 40 CLU-focussed publications. An additional 30 of my publications deal with other ECs we have discovered (some of these reports include comparisons with CLU). I have generated a large body of evidence to support an integrated model I proposed in which, in body fluids, CLU and other ECs inhibit protein aggregation, neutralise the toxicity of misfolded proteins and facilitate their cell uptake and degradation. We were also the first to discover that in response to stress CLU is redirected into the cell cytosol, where it is now known to stimulate autophagy to preserve cell viability. These life supporting roles are reflected in demonstrations that ablation of the CLU gene in mice leads to significant worsening of the consequences of a variety of diseases and experimental insults. Mutations in the human CLU gene are also one of the highest known risk factors for Alzheimer’s disease.

The complex post-translational processing of CLU and its very potent chaperone activity presented a series of substantial technical challenges to its recombinant expression. We invested years of work to recently complete development of a tractable expression/purification system that provides both high-yield and single-step purification of fully post-translationally processed and chaperone-active recombinant CLU, and engineered CLU mutants. Importantly, together with our collaborators at the University of Cambridge we have also designed and generated recombinant designed antibodies that when used together with mutational analysis will allow us, for the first time, to unambiguously identify regions of the CLU molecule critical to its chaperone function (work still in progress). We have also recently published studies in which we (a) developed a technique to rationally select previously unknown ECs from body fluids, and used this to discover five new putative ECs with important biological functions, and (b) identified the first two known ECs that preferentially interact with only amyloid-forming proteins.