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Genetic and molecular basis of copper homeostasis and human inherited and acquired diseases involving disturbances in copper homeostasis with emphasis on Alzheimer's disease

Professor Jim Camakaris

Copper is an essential trace metal for aerobic life being required by a number of key metalloenzymes. However it is also potentially toxic. The paradox of an essential trace metal being toxic to the cell in larger amounts can be resolved by the existence of specific transport, storage and detoxification mechanisms encoded by several genes. 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 whilst copper regulates Amyloid Precursor Protein. Excess extracellular copper bound to beta amyloid may result in functional copper deficiency in neurons leading to oxidative stress both inside and outside cells 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.

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A primary hippocampal neuron in culture-an important tool in studies of neurodegenerative diseases.


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"). ATP7A is a crucial copper transporter being 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. ATP7A has recently been found to be involved in the mechanism of resistance to important drugs used in cancer chemotherapy, and to be involved in cell migration (a key process in cancer).

We discovered a novel system of regulation for metal transport proteins whereby the ligand (Cu) induces the intracellular trafficking of its own transporter (ATP7A) from the trans-Golgi network (TGN) to the plasma membrane (PM).  At the TGN, ATP7A 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 ATP7A protein recycle back to the TGN. Furthermore, we have found that in polarized epithelial cells, when Cu levels increase, ATP7A traffics from the TGN and is targeted to the basolateral membrane which is consistent with ATP7A functioning to pump copper from the gut epithelial cells to the blood. We recently discovered that ATP7A is phosphorylated by kinases when copper is elevated. This is an important breakthrough, as Cu-responsive kinase phosphorylation may provide signalling mechanisms, which are involved in localisation/trafficking of ATP7A, and are likely to be part of a more general signalling response pathway(s) which allows cells to respond to changes in copper levels.

In collaborative studies, we are investigating the role of phosphorylation of metal binding sites we have identified in ATP7A and in particular how phosphorylation modulates the folding of these sites (and hence affinity for copper) using the exciting approach of Supercomputer Molecular Dynamics Simulations.

We recently published the discovery of copper-responsive trafficking of Amyloid Precursor Protein (APP) of Alzheimer’s disease. We found copper-responsive relocalisation of APP from the trans- Golgi network to other compartments including the plasma membrane. The unravelling of the mechanisms underlying this will be critical in understanding the role of copper in Alzheimer’s disease and will inform on novel approaches for treatment of Alzheimer’s disease given APP at the plasma membrane is processed by a pathway that does not result in the toxic beta amyloid. 

We are located at the Melbourne Brain Centre.

Recent Publications

Camakaris Lab Personnel

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