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.
Control Of Catecholamine Synthesis And Secretion By Angiotensin II.
Funder
National Health and Medical Research Council
Funding Amount
$271,650.00
Summary
In the stress response the catecholamines, including adrenaline, are secreted by the adrenal gland and the brain. This leads to the synthesis of new catecholamines in order to replace those that were lost. Synthesis of catecholamines is controlled by the activity and the amount of the enzyme tyrosine hydroxylase. Catecholamine synthesis and secretion is therefore a fundamental physiological process. This can be controlled by a number of mechanisms, including hormones such as angiotensin II. Angi ....In the stress response the catecholamines, including adrenaline, are secreted by the adrenal gland and the brain. This leads to the synthesis of new catecholamines in order to replace those that were lost. Synthesis of catecholamines is controlled by the activity and the amount of the enzyme tyrosine hydroxylase. Catecholamine synthesis and secretion is therefore a fundamental physiological process. This can be controlled by a number of mechanisms, including hormones such as angiotensin II. Angiotensin II has a number of functions including the control of blood pressure and body fluid homeostasis. Angiotensin II acts on the adrenal glands, the sympathetic nerves and the brain to produce these effects. It does so by increasing the secretion of catecholamines and these in turn modulate blood pressure and fluid homeostasis. The mechanism(s) whereby angiotensin II induces catecholamine secretion is not known, nor is it known how this leads to increased tyrosine hydroxylase activity and synthesis. The aim of this grant is therefore to determine how angiotensin II induces the activation of tyrosine hydroxylase, the secretion of catecholamines and the synthesis of new tyrosine hydroxylase. The significance of this work is that it will allow us to better understand how angiotensin II works and it will provide insights into the generation and control of hypertension and the mechanisms of the stress response. It is known that the pathways involved in angiotensin II stimulation of catecholamine secretion can be blocked by inhibitors of protein kinases and this leads to a reduction in blood pressure. It is therefore likely that this work will have therapeutic implications.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
SRY: A Risk Factor For Parkinson’s Disease In Men?
Funder
National Health and Medical Research Council
Funding Amount
$514,015.00
Summary
Parkinson’s disease is a debilitating neurological disorder that affects over 70,000 Australians. This project will test the novel concept that the male sex-determination gene SRY is a risk factor for Parkinson’s disease in men. A potential implication of the work is that it will help explain why men are more susceptible to Parkinson’s disease than women, and may also provide avenues for the development of novel therapeutics for this condition.
A Novel Mechanism For The Maintenance Of Catecholamine Synthesis
Funder
National Health and Medical Research Council
Funding Amount
$356,250.00
Summary
Stress causes an acute response that prepares us for flight or a fight and an adaptive response that requires days to establish. The catecholamines, including adrenaline, noradrenaline and dopamine are critical to both the acute and adaptive stress responses. They are secreted from cells at the level of the nervous system and the adrenal gland. We all respond differently to stress and if we do not cope we can become hypertensive or depressed. These pathologies require drug management and the dru ....Stress causes an acute response that prepares us for flight or a fight and an adaptive response that requires days to establish. The catecholamines, including adrenaline, noradrenaline and dopamine are critical to both the acute and adaptive stress responses. They are secreted from cells at the level of the nervous system and the adrenal gland. We all respond differently to stress and if we do not cope we can become hypertensive or depressed. These pathologies require drug management and the drugs all affect the catecholamine systems. Tyrosine hydroxylase controls catecholamine synthesis and it is activated in both the acute and adaptive phases of the stress response in order to replace catecholamines that have been secreted. Tyrosine hydroxylase is activated by protein phosphorylation in the acute phase and by the synthesis of new tyrosine hydroxylase in the adaptive phase. We have now discovered an additional and novel phase that we refer to as sustained tyrosine hydroxylase activation. This phase spans at least the period between the acute (mins) and adaptive phases (days). It involves the sustained phosphorylation of tyrosine hydroxylase and its mechanism appears to differ from the other two phases. In this project we will answer three questions. Does sustained tyrosine hydroxylase activation: 1 Occur in response to many stimuli and in many catecholamine cell types? 2 Occur by a single mechanism, different to the other phases, in all circumstances? 3 Play a role in the control of blood pressure and depression? This project will provide fundamental data about the mechanisms and consequences of sustained tyrosine hydroxylase activation, which is a part of the stress response not previously discovered. The data may impact on the way we design drugs to control stress responses, including antidepressants and antihypertensives.Read moreRead less