Research

Genetic and molecular basis of copper homeostasis and human genetic diseases and acquired diseases involving disturbances in copper homeostasis (eg. Alzheimer’s disease)

Professor Jim Camakaris

Copper is toxic to biological systems, yet it is an essential trace element for aerobic life being required by a number of key metalloenzymes. The paradox of an essential trace element being toxic to the cell in larger amounts can be resolved by the existence of specific transport, storage and detoxification mechanisms. Maintaining a correct copper balance, ie homeostasis, is critical.

There are a number of diseases due to acquired or inherited copper deficiency or copper toxicity states. In addition, chronic marginal copper deficiency may be an important cofactor in cardiovascular disease and osteoporosis. Disturbances in copper metabolism are linked to several neurodegenerative diseases in humans including Alzheimer's disease, prion disease (eg. mutant prion protein involved in "mad cow" disease) and forms of motor neuron disease. We and other investigators have published evidence that Amyloid Precursor Protein or a cleavage product, beta amyloid (which accumulates in the Alzheimer’s disease brain), is involved in copper homeostasis. Excess extracellular copper bound to beta amyloid may result in functional copper deficiency leading to oxidative stress and hence Alzheimer’s disease brain pathology. We believe that copper enters cells and is distributed within cells bound to carriers in a series of regulated steps analogous to a metabolic pathway. Detoxification systems (some inducible) also exist to cope with conditions of copper excess.

Our strategy is to use mutants in which copper metabolism is disturbed and ‘knockdown” of candidate genes in order to dissect the pathways of copper metabolism and to understand copper homeostasis and its regulation. Menkes disease is a potentially lethal X-linked recessive disorder of copper metabolism in humans. The Menkes (MNK, ATP7A) gene has been cloned and encodes a transmembrane  Cu-translocating P-type ATPase (ie: an ATP-driven Cu "pump"). MNK is required for delivery of copper to several Cu-dependent enzymes for absorption of copper from the gut, reabsorption of copper in the kidney and for transfer of copper across the blood-brain barrier. MNK has recently been found to be involved in the mechanism of resistance to important drugs used in cancer chemotherapy.

We discovered a novel system of regulation for metal transport proteins whereby the ligand (Cu) induces the intracellular trafficking of its own transporter (MNK) from the trans-Golgi network (TGN) to the plasma membrane (PM).  At the TGN, MNK delivers copper to copper-dependent enzymes in the secretory pathway. Trafficking involves vesicles and we propose that the overall mechanism provides a swift way of eliminating excess copper (copper is essential for a number of enzymes but excess copper is toxic and cells must get rid of it). When copper drops to safe levels, vesicles containing MNK protein recycle back to the TGN. Furthermore, we have discovered that in polarized epithelial cells, when Cu levels increase, MNK traffics from the TGN and is targeted to the basolateral membrane which is consistent with MNK functioning to pump copper from the gut epithelial cells to the blood. We have recently discovered that MNK is phosphorylated by kinases when copper is elevated. This is an important finding, as Cu-responsive kinase phosphorylation may provide a signalling mechanism, which is involved in localisation/trafficking of MNK, and may be part of a more general signalling response pathway(s) which allows cells to respond to changes in copper levels.

Research Programs:

1. Regulation of the  localisation and trafficking of the Menkes (MNK; ATP7A) copper translocating P-type ATPase

2. Copper and Alzheimer's Disease

3. The role of copper and zinc in age-related macular degeneration

4. Use of Drosophila as a model organism to investigate copper homeostasis and Alzheimer’s disease.

Recent Publications

Camakaris Lab Personnel