Copper Pathways Are Altered In Parkinson’s Disease: Implications For Cell Vulnerability
Funder
National Health and Medical Research Council
Funding Amount
$341,398.00
Summary
The cause of brain cell death in Parkinson’s disease is unknown but we have shown that copper levels are reduced in the vulnerable brain regions in this disorder. As copper is vital for the normal function of key brain proteins we suggest that reduced copper contributes to cell damage in vulnerable brain regions. This project investigates why brain copper levels are reduced in the Parkinson’s disease brain and the consequences of this change for brain cell function and survival.
Development Of Therapeutic Copper Delivery Agents For Menkes Disease
Funder
National Health and Medical Research Council
Funding Amount
$651,467.00
Summary
Menkes disease does not currently have an effective treatment. The disease is caused by genetic defects that reduce copper transport into the brain and cause mental retardation and death. We have developed drugs that deliver copper into the brain and should cure Menkes disease. We aim to demonstrate that our drugs are effective in mice that have the same genetic defect as patients. Successful results will allow us to begin treating Menkes disease patients to determine if we can cure the disease.
Elucidation Of Trafficking Of The Menkes (MNK;ATP7A) Copper-transporting ATPase In Epthelial Cells
Funder
National Health and Medical Research Council
Funding Amount
$457,267.00
Summary
Copper is an essential trace element for all organisms. Copper is needed for many processes including energy metabolism, the making and maintenance of strong bones and arteries with sufficient elasticity, the synthesis of chemical transmitters in the brain and for the reactions which remove toxic free radicals. Copper is also used by the proteins involved in important neurological diseases including Alzheimers disease and mad cow disease. Menkes disease is an inherited and usually lethal copper ....Copper is an essential trace element for all organisms. Copper is needed for many processes including energy metabolism, the making and maintenance of strong bones and arteries with sufficient elasticity, the synthesis of chemical transmitters in the brain and for the reactions which remove toxic free radicals. Copper is also used by the proteins involved in important neurological diseases including Alzheimers disease and mad cow disease. Menkes disease is an inherited and usually lethal copper deficiency disorder in humans, and the diverse and detrimental symptoms of this disease related to organs and tissues described above is a stark indicator of the essentiality of copper. We have carried out extensive research on Menkes disease and in particular the Menkes protein which in normal individuals plays a major role in maintaining the copper balance in cells, i.e. enough copper to satisfy nutritional needs of cells but not too much which causes toxicity. The normal Menkes protein catalyses the transport of copper across membranes of cells to the areas where it is needed by copper-dependent enzymes and is essential for copper absorption into the body from the gut. The normal Menkes protein functions as a molecular pump. We have discovered that this protein can sense copper concentrations in the cell and when these reach potentially toxic levels it can move (traffic) via small vesicles to the plasma membrane which surrounds cells. There it pumps the excess copper out of the cell and returns to its original location. Our studies are directed to understanding the molecular mechanisms which permit this remarkable protein to achieve a copper balance in living cells. The findings will be of major significance in understanding and treating acquired and inherited diseases involving copper deficiency or copper toxicity including osteoporosis, cardiovascular disease, and Alzheimer's disease.Read moreRead less
Copper is an essential trace element with the potential for toxicity. Copper deficiency can be fatal to developing animals due to the multiple organ abnormalities caused by the reduced activity of important copper containing enzymes. Dietary copper deficiency can cause iron unresponsive anaemia in children and may contribute to heart disease and connective tissue defects in adults. A variant form of a copper containing protein is thought to contribute to Alzheimer's disease and the affected prot ....Copper is an essential trace element with the potential for toxicity. Copper deficiency can be fatal to developing animals due to the multiple organ abnormalities caused by the reduced activity of important copper containing enzymes. Dietary copper deficiency can cause iron unresponsive anaemia in children and may contribute to heart disease and connective tissue defects in adults. A variant form of a copper containing protein is thought to contribute to Alzheimer's disease and the affected protein in mad cow disease may normally play a role in copper biology of the brain. Given the importance of copper for normal health and the potential for toxicity, the levels of copper in the body are tightly regulated. There are two main sites for this regulation: the uptake of dietary copper across the intestine and the excretion of excess copper into the bile. This proposal addresses the molecular control of copper uptake in the intestine. Much of our understanding about the regulation of the uptake of copper from dietary sources was obtained prior to the era of modern molecular biology. Prof. Mercer's laboratory has recently made significant discoveries into the molecular basis of copper metabolism in human cells. Based on these findings and finding of others about copper metabolism in yeast, we have proposed a model incorporating these newly described molecules to explain how the body might regulate the uptake of copper in the intestine. We propose to investigate this model using cell culture models of the intestine and in mouse models. These studies will extend our knowledge of copper biology and may provide insight for potential treatments of copper related disorders.Read moreRead less
Identification And Characterisation Of Novel Copper Homeostasis Genes And Proteins
Funder
National Health and Medical Research Council
Funding Amount
$70,307.00
Summary
Copper is an essential nutrient that is also toxic when in excess. Specific mechanisms exist to regulate copper levels and these are conserved across many species. Disrupted copper regulation contributes to many diseases including: cardiovascular disease, osteoporosis and Alzheimer’s. I aim to identify and characterise novel copper regulatory proteins using the model organism Drosophila (vinegar fly) together with human cultured cells as a foundation for work to prevent or treat these diseases.
The Role Of Presenilin In Metal Homeostasis And Alzheimers Disease
Funder
National Health and Medical Research Council
Funding Amount
$86,335.00
Summary
Presenilin, a protein involved in Alzheimer’s disease (AD), may regulate copper and zinc levels. Copper and zinc are essential nutrients however a deficiency or excess can cause disease. Promising metal-altering AD drugs, are in various stages of clinical trial. I aim to characterize the interaction of Presenilin and metals using both mouse and cultured human cell models that are deficient in Presenilin. Understanding this interaction should lead to better drug design and treatment of AD.
Molecular And Cellular Studies Of The Copper-transporting ATPases Affected In Menkes And Wilson Diseases
Funder
National Health and Medical Research Council
Funding Amount
$558,300.00
Summary
Copper is an element that is essential for life but is highly toxic in excess. Because of this, the regulation of copper uptake, distribution in the body and excretion of excess is a very tightly regulated process. Until recently little was known about the molecular basis of this process. Two genetic disorders that show these two aspects of copper are Menkes disease (deficiency) and Wilson disease (toxicity). Both diseases are caused by mutations in similar copper pumping proteins. Our research ....Copper is an element that is essential for life but is highly toxic in excess. Because of this, the regulation of copper uptake, distribution in the body and excretion of excess is a very tightly regulated process. Until recently little was known about the molecular basis of this process. Two genetic disorders that show these two aspects of copper are Menkes disease (deficiency) and Wilson disease (toxicity). Both diseases are caused by mutations in similar copper pumping proteins. Our research is trying to establish the molecular mechanisms used in the body to control copper metabolism. We made a major breakthrough in 1993 with the isolation of the gene affected in Menkes disease, and we continue to be one of the leading groups in the world in studying the molecular mechanisms that handle copper, and the importance of these mechanisms in health and disease. Research into the biology of copper has become much more important following the recent discoveries of the involvement of the metal in such important neurodegenerative conditions such as Alzheimer's, Mad Cow, and Parkinson's diseases. Health effects from the lack of copper may be widespread also, copper deficiency is suspected to contribute to some common diseases, such as cardiovascular problems and osteoporosis. Our research is providing information about copper transport mechanisms that are necessary for the understanding of, and may lead to better treatment and diagnosis of common and important diseases. In this grant we propose to continue our studies into the molecular signals that control the copper pumps, that make the regulation of copper metabolism possible. We also will use various test systems for studying the effect of mutations on the activity of these proteins and relate these effects to the type of disease produced in patients.Read moreRead less
Modulation Of Neurotherapeutic Cell Signalling Pathways By Metallo-complexes As A Treatment For Alzheimers Disease.
Funder
National Health and Medical Research Council
Funding Amount
$653,113.00
Summary
Alzheimer's disease (AD) is an enormous burden on the Australian health care system . We have begun to investigate therapeutic treatments based on triggering protective cell signalling pathways with metal-based compounds. These compounds trigger the activation of a signalling cascade resulting in inhibition of AD-associated symptoms. In this proposal we will further investigate how these compounds modulate specific receptors and cellular kinase activity to protect neurons in the AD brain.