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award-recipient-2021-Dr-Frederick-Partridge

Dr. Frederick Partridge

The pathological role of copper in antitrypsin deficiency-related liver disease


Background:

α1-Antitrypsin (AAT) deficiency has a clear genetic basis: mutations in the gene encoding AAT. Polymerogenic variants of AAT can cause liver disease. However, despite sharing the same polymerogenic PiZZ genotype, only around a third of adults show clinically significant liver fibrosis. We hypothesise that detailed knowledge of the mechanisms by which AAT misfolding perturbs liver cell homeostasis will provide a better understanding the basis for this pathological variability.

We know that polymer accumulation leads to impaired protein mobility in the ER, physically-separated membrane-bound inclusions, susceptibility to ER stressors such as tunicamycin, involvement of protective pathways such as autophagy, and degradation of AAT by the proteosome and lysosome. We have been seeking to identify new mechanisms by which polymerogenic AAT variants cause liver pathology by conducting a genetic screen in a C. elegans model of Z AAT. The results from this screen led to a new hypothesis that I will test in this project: that copper can interact with antitrypsin and lead to effects that mediate, at least in part, the pathological consequences of Z mutant AAT.

 

Aims:

  1. Determine the influence of copper on AAT polymerization
  2. Test the hypothesis that copper binding to ZAAT causes oxidative stress
  3. Test the hypothesis that copper chelating drugs can protect cells from ZAAT damage.

 

Curriculum vitae Dr. Frederick Partridge

Undergraduate degree in biochemistry from the University of Oxford, followed by a DPhil, also at the University of Oxford, in the lab of Prof Jonathan Hodgkin, studying the genetics of host-pathogen interactions in the nematode C. elegans. He is currently a Senior Research Fellow at University College London, working with Prof David Lomas and Prof David Sattelle. His recent focus has been the building of an image-based high-throughput screening platform and its application for genetic and phenotypic small molecule screening in the areas of human misfolding diseases including α1-antitrypsin deficiency, and parasitic diseases.