Phosphatase Regulators Mediate Long-term Changes In Presynaptic Terminals
Funder
National Health and Medical Research Council
Funding Amount
$984,163.00
Summary
The strength of communication between each nerve cell in the brain depends on how active that nerve cell has been. This enables the brain to be adaptable and is a way for the brain to set up circuits that underlie how we learn and remember. More or less release of chemical messengers (neurotransmitters) into nerve cell junctions changes the strength of nerve cell communication. We have discovered a new chemical signalling pathway controlling neurotransmitter release.
Protein Phosphatase 2A Methylation: Regulation And Functional Significance For Tauopathies
Funder
National Health and Medical Research Council
Funding Amount
$470,713.00
Summary
Clinical studies have revealed that low blood levels of the vitamin folate are a risk factor for cognitive impairment, depression and dementia, which are prevalent in the elderly. Deregulation of the protein tau is a key event in Alzheimer’s disease pathogenesis. This project will utilize cell culture and aged mouse models to determine how alterations in folate status and deregulation of protein phosphatase 2A affect the regulation of tau and other key brain processes that become altered in Alzh ....Clinical studies have revealed that low blood levels of the vitamin folate are a risk factor for cognitive impairment, depression and dementia, which are prevalent in the elderly. Deregulation of the protein tau is a key event in Alzheimer’s disease pathogenesis. This project will utilize cell culture and aged mouse models to determine how alterations in folate status and deregulation of protein phosphatase 2A affect the regulation of tau and other key brain processes that become altered in Alzheimer’s disease.Read moreRead less
Differential Regulation Of Two Modes Of Exocytosis By Protein Phosphatases
Funder
National Health and Medical Research Council
Funding Amount
$399,750.00
Summary
The release of signals from nerve endings (exocytosis) is of fundamental importance to nervous system function. The recent recognition that nerve cells can release transmitter by at least two distinct modes of exocytosis has led to the need for a deeper understanding of the mechanisms that regulate exocytosis. Our identification of the key role played by two enzymes, PP2A and PP2B, represents a major insight into the molecular mechansisms regulating this process. The experiments will lead to the ....The release of signals from nerve endings (exocytosis) is of fundamental importance to nervous system function. The recent recognition that nerve cells can release transmitter by at least two distinct modes of exocytosis has led to the need for a deeper understanding of the mechanisms that regulate exocytosis. Our identification of the key role played by two enzymes, PP2A and PP2B, represents a major insight into the molecular mechansisms regulating this process. The experiments will lead to the identification of how PP2A and PP2B are regulated at the molecular level and the targets that are important in the control of exocytosis. The project will also develop new tools to specifically manipulate the two modes of exocytosis in order to understand their contribution to normal and pathological neurotransmission. Strong stimulation of exocytosis is associated with learning and memory in normal brain and neuronal damage under certain pathological conditions. Since switching from 1 mode of exocytosis to another is also induced by strong stimulation, an understanding of the molecular mechanisms that control the different modes of exocytosis may eventually lead to clinical applications.Read moreRead less
The Cystine Glutamate Antiporter And Classical Glutamate Transporters In Normal And Pathological Brains And Retinae
Funder
National Health and Medical Research Council
Funding Amount
$416,000.00
Summary
This project will examine the role of a system that transports a toxic neurotransmitter, glutamate out of cells where it is relatively harmless, into the space surrounding nerve cells where it can be highly toxic. Previous models for the aberrant release of glutamate under pathological conditions such as strokes, have relied on the notion that other specialised glutamate transporters which normally work to remove glutamate from the space surrounding nerve cells, actually reverse their direction ....This project will examine the role of a system that transports a toxic neurotransmitter, glutamate out of cells where it is relatively harmless, into the space surrounding nerve cells where it can be highly toxic. Previous models for the aberrant release of glutamate under pathological conditions such as strokes, have relied on the notion that other specialised glutamate transporters which normally work to remove glutamate from the space surrounding nerve cells, actually reverse their direction of action and release glutamate. The current study investigates a transport system (called the cystine-glutamate antiporter) where the normal direction of action is to release glutamate. This system has been overlooked despite evidence that it could be involved in releasing glutamate and thus contribute to the death of nerve cells in a variety of human pathologies including glaucoma of the eye, epilepsy, and brain damage that occurs when the blood supply to the brain is interrupted, such as after a heart attack. This study examines both human tissues and animal models of disease states to determine if similar transport systems are present and if the cystine-glutamate antiporter might contribute to human nervous diseases. The function and distribution of the cystine-glutamate antiporter will be compared with classical transporters, under normal and pathological conditions, including situations where we have shown that it is possible to experimentally perturb normal glutamate transporter expression.Read moreRead less