Human Tyrosine Hydroxylase Isoforms And Susceptibility Of Dopaminergic Neurons To Degeneration In Parkinson's Disease
Funder
National Health and Medical Research Council
Funding Amount
$359,683.00
Summary
In Parkinson's disease there is major loss of the dopaminergic neurons of the substantia nigra. We are investigating how the control of dopamine synthesis may affect the differential loss of dopaminergic neurons in Parkinson's disease. Understanding why certain dopaminergic die in Parkinson's disease and others do not will help the development of new treatment strategies for Parkinson's disease.
Innovative And Multi-disciplinary Treatment Strategies For Secondary Degeneration Following Neurotrauma
Funder
National Health and Medical Research Council
Funding Amount
$455,452.00
Summary
Following injury to the central nervous system the damage spreads into nearby areas, leading to worse outcomes for the patient. The research conducted during this Fellowship will ensure that promising treatment strategies to prevent spreading damage are used in the best way, and will determine the mechanism of action of these treatments.
Optimising Combinations Of Calcium Channel Inhibitors For Treatment Of Secondary Degeneration After Neurotrauma
Funder
National Health and Medical Research Council
Funding Amount
$679,772.00
Summary
Traumatic injury to the central nervous system is made worse by damage that spreads away from the initial point of impact. Excess calcium entering cells is a key contributor to spreading damage but treatment with single calcium channel inhibitors has been disappointing. We will use combinations of calcium channel inhibitors to block multiple calcium channels and ensure the optimised combination is effective in clinically relevant models of neurotrauma.
Parkinson's Disease (PD) is one of the most common neurodegenerative disorders. Its incidence increases steadily with age affecting approximately 1% of the population at age 65 and up to 5% by the age of 85. At the time of diagnosis, patients suffer from a range of motor impairments that worsen over time. Pathologically these patients are characterised by the accumulation of a protein known as alpha-synuclein in specific types of nerve cells in their brain. However, the function of this protein ....Parkinson's Disease (PD) is one of the most common neurodegenerative disorders. Its incidence increases steadily with age affecting approximately 1% of the population at age 65 and up to 5% by the age of 85. At the time of diagnosis, patients suffer from a range of motor impairments that worsen over time. Pathologically these patients are characterised by the accumulation of a protein known as alpha-synuclein in specific types of nerve cells in their brain. However, the function of this protein is unknown. This proposal will clarify the role of alpha-synuclein in PD and normal CNS function and provide new potential therapeutic targets for the treatment of PD and other neurodegenerative disorders in which oxidative stress, excitotoxicity and central nervous system trauma have been implicated.Read moreRead less
Differential Regulation Of Human Tyrosine Hydroxylase Isoforms And The Development Of Parkinson's Disease
Funder
National Health and Medical Research Council
Funding Amount
$325,591.00
Summary
Parkinson's disease is a common neurodegenerative disease whose major feature is loss of a dopamine containing nerves in a part of the brain called the substantia nigra. Loss of nerves within the substantia nigra is not uniform, but firstly and primarily affects the ventral cells, suggesting that particular dopaminergic neurons are more vulnerable to the disease process. A key to understanding Parkinson's disease would be to work out why these cells are more susceptible to degeneration than othe ....Parkinson's disease is a common neurodegenerative disease whose major feature is loss of a dopamine containing nerves in a part of the brain called the substantia nigra. Loss of nerves within the substantia nigra is not uniform, but firstly and primarily affects the ventral cells, suggesting that particular dopaminergic neurons are more vulnerable to the disease process. A key to understanding Parkinson's disease would be to work out why these cells are more susceptible to degeneration than other dopaminergic cells in the brain. Tyrosine hydroxylase controls the rate of dopamine synthesis. Humans are unique in that they contain four isoforms of tyrosine hydroxylase and therefore they have the potential to alter the regulation of dopamine synthesis in ways that other species do not. Recent developments in our laboratories have suggested that particular isoforms of tyrosine hydroxylase may have either a role in the susceptibility of dopaminergic neurons to degeneration in Parkinson's disease or a role in the timing of the symptoms of the disease. We have demonstrated differences in the distribution of the human TH isoforms within the substantia nigra, with certain isoforms being more prevalent in the susceptible ventral cells. We have also shown that there are major differences in the regulation of the four human tyrosine hydroxylase isoforms. Some isoforms will be more sensitive to conditions that occur with high frequency stimulation of neurons and some to low frequency sustained stimulation. This would provide a mechanism by which differential distribution of the human TH isoforms would result in altered dopamine synthesis in different parts of the human brain and this may in turn lead to either increased susceptibility to, or earlier appearance of symptoms of, Parkinson's disease.Read moreRead less
Huntington’s disease (HD) is a devastating neurodegenerative disorder which shares several features with Alzheimer’s and Parkinson’s disease (i.e. dementia-like cognitive deficits). There is currently no cure for HD. Using a mouse model of HD and a combination of relevant drugs (i.e. N-Acetylcysteine and deferiprone) targeting two distinct levels of the cascade of events leading to HD, we will slow down the progression of the disease and correct dysfunctions within the brain.
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
Professor Ashley Bush has extensively researched the contribution of metal biochemistry to Alzheimer�s and Parkinson�s diseases. In the current proposal he will lead the clinical testing of a new drug that combats the abnormal accumulation of metals in Alzheimer�s brain pathology, he will search for abnormal metal-interactions with blood proteins as a potential predictive test, and he will study the roles of various brain proteins in regulating metal levels to maintain healthy function.
Astrocytic Contributions To Tissue Damage And Dysfunction In Stroke
Funder
National Health and Medical Research Council
Funding Amount
$275,810.00
Summary
Stroke is a primary cause of disability and death in adults. The symptoms of stroke arise from damage to brain tissue following disruptions to blood flow. At present, there are few options for treatments to limit the extent of tissue damage and the consequent disruption to function. Although, there have been considerable advances in understanding the cellular and molecular processes underlying the tissue damage, many issues are unresolved. A better understanding of these processes is likely to o ....Stroke is a primary cause of disability and death in adults. The symptoms of stroke arise from damage to brain tissue following disruptions to blood flow. At present, there are few options for treatments to limit the extent of tissue damage and the consequent disruption to function. Although, there have been considerable advances in understanding the cellular and molecular processes underlying the tissue damage, many issues are unresolved. A better understanding of these processes is likely to open up new avenues for ameliorating damage and improving outcomes for stroke patients. Astrocytes are one of the major populations of cells in the brain. They play key roles in supporting normal brain function and protecting nerve cells in the brain. Because of their many functions, these cells offer considerable potential as a therapeutic target in stroke. Unfortunately, the responses of astrocytes in this disorder are poorly understood due partly to a lack of techniques to distinguish their contributions from that of other cells in the brain. We have recently designed a novel system using antibodies to deliver genes into selected populations of nerve cells in the nervous system and thus to selectively alter the function of these cells. In the proposed study, we will adapt this technique to selectively modify gene expression in astrocytes. We will then apply the procedure to determine the consequences of altering key functions in astrocytes on the brain damage and behavioural changes that develop in an animal model of stroke. The successful completion of this research will provide a powerful means to investigate the function of astrocytes, not only in diseases such as stroke but also in normal brain. We will also gain novel insights into the astrocytic role in the damage and dysfunction resulting from stroke that have potential applications in developing new therapies.Read moreRead less