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Biological inorganic chemistry of copper in the early ubiquitination pathways
The ubiquitination pathway is an essential post-translational modification (poly-ubiquitination) process for subsequent degradation of proteins by the proteasome. Failures in this pathway may explain accumulation of proteins observed in many aged-related neurodegenerative diseases (such as Alzheimer’s, Parkinson’s and Huntington’s diseases). The pathway involves sequential actions by three classes of enzymes (E1, E2, E3) plus Mg-ATP.
Recent work by Opazo, Bush et al discovered that “physiological levels” of copper can regulate ubiquitination levels and protein degradation in tissue culture. Certain E2 enzymes were identified as the main targets of copper binding and regulation. This is a significant discovery, since copper homeostasis has long been recognized as a key contributing factor in cellular protein clearance. An understanding of the role of copper at the atomic level is essential to a molecular understanding of these key processes.
This project will express and isolate the enzyme targets identified by the in vivo study in order to undertake a systematic structure-function study to understand the molecular role of copper in ubiquitination.
(1) Vilchez, D.; Saez, I.; Dillin, A., The role of protein clearance mechanisms in organismal ageing and age-related diseases, Nat. Commun. 2014, 5, 5659.
(2) Gadhave, K., et al, The ubiquitin proteasomal system: a potential target for the management of Alzheimer's disease, J. Cell. Mol. Med. 2016, 20, 1392-1407.
Neurochemistry of Metal Ions
Metal ions play vital roles in brain development and function. But they are also toxic and their mishandling in brain cells are associated with multiple neurodegenerative diseases.
My laboratory focuses on the biological inorganic chemistry of metal ions (Cu, Zn, Fe in particular) in neurodegeneration.
We aim for a molecular understanding of the functional roles of these neuro-metals in healthy brain and in disease states.
All Projects by this LabMolecular mechanism of copper transporting ATPasesBiological inorganic chemistry of copper in the early ubiquitination pathways
Dr Lachlan Thompson
Prof David Finkelstein
Scientists in the Neurodegeneration division interrogate how neurones live, die and can be rescued to improve brain function in degenerative conditions such as Parkinson’s and Motor Neuron Diseases. There is no effective treatment for Motor Neurone Disease and the incidence of Parkinson’s Disease is rising alarmingly in our aging community. Gene abnormalities, energy deprivation, toxic rubbish accumulation and inflammation all contribute to a toxic environment for brain cells. Our teams study these events in animal models and cultured cells, with a view to translating knowledge into new therapies for human patients.