Glutathione is a natural antioxidant, which is known to protect cells in the body from chemical damage. A small part of the glutathione in cells is found in the mitochondria, a structure that is involved in producing the chemical energy needed for normal cell function. The mitochondria are also involved under some circumstances in promoting the death of cells. Although glutathione in general has been well studied, much less attention has been paid to the function of glutathione in mitochondria, ....Glutathione is a natural antioxidant, which is known to protect cells in the body from chemical damage. A small part of the glutathione in cells is found in the mitochondria, a structure that is involved in producing the chemical energy needed for normal cell function. The mitochondria are also involved under some circumstances in promoting the death of cells. Although glutathione in general has been well studied, much less attention has been paid to the function of glutathione in mitochondria, particularly in cells from the brain. Our recent studies indicate that this mitochondrial pool of glutathione is particularly important in limiting the death of cells from the brain when exposed to damaging substances that are increased in some diseases. Thus, the capacity of mitochondrial glutathione to deal with such substances might be a factor in determining the extent of cell loss in the brain, which is an important determinant of symptoms in some of the major neurological diseases. Consistent with this possibility, we have obtained evidence indicating that decreases in glutathione in the mitochondria contribute to the cell death and brain damage that results from a stroke. In our proposed studies, we will investigate the function of mitochondrial glutathione in the two major cell populations from the brain, neurons and astrocytes. We will characterise the protective role of the glutathione and investigate how it enters the mitochondria and what factors influence the amount that is present. This will provide new insights into the function of glutathione in the mitochondria and could also suggest novel approaches for manipulating this antioxidant pool. We will also study models of stroke and some related brain disorders to more directly test the role of this antioxidant in disease and to assess whether manipulating the content of glutathione in the mitochondria has the potential to reduce damage and improve function in these disordersRead moreRead less
How Does Iron Accumulation Affect Parkinson’s Disease And What Controls It?
Funder
National Health and Medical Research Council
Funding Amount
$545,517.00
Summary
Currently there is no cure for Parkinson's disease, and although we have a number of treatments to manage the disease there is an urgent need for a further understanding of the disease process. This proposal will investigate the critical role that iron plays in the cause of neuronal cell death that results in Parkinson's disease, and will investigate methods for regulating metal levels in the brain.
A New Function For An Old Enzyme: Src Protein Kinase Directs Excitotoxic Neuronal Death In Stroke
Funder
National Health and Medical Research Council
Funding Amount
$513,975.00
Summary
In our previous investigation of how brain cells die in patients suffering from stroke, we found that stroke causes aberrant activation of an enzyme called Src in the affected brain cells. Furthermore, this aberrantly activated Src directs the brain cells to undergo cell death. Our proposal, which aims to decipher this neurotoxic mechanism of the aberrantly activated Src will benefit development of new therapeutic strategies to reduce brain damage in stroke patients.
Neuronal Membranes And Connections In Dementia: Targets For Intervention
Funder
National Health and Medical Research Council
Funding Amount
$720,144.00
Summary
This research aims to understand why some people with Mild Cognitive Impairment (MCI) progress to dementia, whilst others do not. The fact that some people’s cognitive abilities can improve provides an opportunity to study the mechanisms that protect their brain cells from the degeneration associated with dementia. Understanding the cellular changes will lead to therapies that can be tested in the lab for individuals.
Regulation Of P75 Death Signalling: How Neurotransmitter- And Neurotrophic- Signals Determine Cell Survival
Funder
National Health and Medical Research Council
Funding Amount
$292,216.00
Summary
Nerve cell survival is dependent on trophic support in the form of growth factors and synaptic input, both of which promote recovery after nerve injury. The survival pathways activated by growth factors are generally well characterised, whereas survival signals activated by synaptic activity are largely unexplored. This proposal aims to discover how synaptic activity prevents nerve cell death by looking at how synaptic activity inhibits the processes active in dying nerve cells.
Structural Investigations Of The Bcl-2 Family Cell Death Apparatus
Funder
National Health and Medical Research Council
Funding Amount
$612,652.00
Summary
Programmed Cell Death is a process by which dangerous cells are removed from the body. Sometimes it goes wrong and causes disease, e.g. cancer cells stay alive when they should die. This project will study a group of proteins that regulate cell death, the Bcl-2 family of proteins, in order to understand the mechanism by which they control the balance of cell life and death. The findings will inform the development of new drugs aimed at regulating cell death in a variety of disease states.
Role Of Synaptogenesis In Developmental Motoneuron Cell Death
Funder
National Health and Medical Research Council
Funding Amount
$361,650.00
Summary
Naturally occurring cell death is an important and necessary event that shapes the developing embryo. It occurs in all organs of the developing body. In the nervous system about 50% of all neurons die at a time when they are making contact with one another or with their target organs. The underlying mechanisms that drive programmed neuronal cell death are not known. One possibility is that the formation of neuronal contacts (synapses) with other neurons and target cells determines the fate of a ....Naturally occurring cell death is an important and necessary event that shapes the developing embryo. It occurs in all organs of the developing body. In the nervous system about 50% of all neurons die at a time when they are making contact with one another or with their target organs. The underlying mechanisms that drive programmed neuronal cell death are not known. One possibility is that the formation of neuronal contacts (synapses) with other neurons and target cells determines the fate of a neuron. The connections of motor neurons with muscle during this period of developmental neuronal cell death is the best model to examine this phenomenon. In this grant we are in an exciting position to be able to address what causes neuronal cell death, as we have a number of mice that lack key molecules needed for the formation of specializations that allow neuronal contacts to be made between motor neurons and their muscle, and with other neurons within the spinal cord. By examining the function of motor neurons, counting them and screening for molecular changes in these mice, we will be able to dissect out the mechanism of how a motor neurons' fate is determined during the period of programmed cell death. The outcomes of this research will enable us to understand how the nervous system is shaped during development and will increase our knowledge about the basis of adult neurodegenerative diseases. For example, the pathology of Alzheimer's is characterised by a breakdown in neuronal connections that ultimately result in neuronal death and a loss of thought processes (cognition).Read moreRead less
Gamma-Secretase Inhibitors As Novel Pharmacological Agents To Target Stroke-induced Brain Injury
Funder
National Health and Medical Research Council
Funding Amount
$441,511.00
Summary
Stroke is the world�s 2nd leading cause of death. In Australia, stroke is the leading cause of serious, long-term disability. Alarmingly, there is a looming stroke epidemic in Australia. There is an urgent need for novel therapies capable of reducing mortality and long-term disability in victims of stroke. We have recently identified gamma-secretase inhibitors (GSIs) as a potent stroke therapy. This project will investigate how GSIs protect against ischaemic stroke at the molecular level.