Lipid Rafts, Amyloid Neurotoxicity And Alzheimer's Disease
Funder
National Health and Medical Research Council
Funding Amount
$318,267.00
Summary
Alzheimer's disease is the major cause of dementia in the elderly. Individuals with Alzheimer's disease exhibit a slow decline in cognition which usually results in prolonged institutionalisation. This creates an enormous burden on society. The project aims to identify mechanisms which cause Alzheimer's disease. Specifically, it will examine how a component of the brain, known as the amyloid protein, contributes to nerve cell degeneration. It is hoped that by identifying these mechanisms, new ta ....Alzheimer's disease is the major cause of dementia in the elderly. Individuals with Alzheimer's disease exhibit a slow decline in cognition which usually results in prolonged institutionalisation. This creates an enormous burden on society. The project aims to identify mechanisms which cause Alzheimer's disease. Specifically, it will examine how a component of the brain, known as the amyloid protein, contributes to nerve cell degeneration. It is hoped that by identifying these mechanisms, new targets for drug development will be found.Read moreRead less
Regulation Of Synaptic Vesicle Biogenesis For Synaptic Transmission
Funder
National Health and Medical Research Council
Funding Amount
$339,115.00
Summary
The overall aim is to better understand the molecular processes of nerve cell communication during learning, memory and abnormal brain activity that cause neurological diseases. The supply and generation (biogenesis) of synaptic vesicles (SVs) in nerve cells is critical to sustain neurotransmission. It requires complex protein interactions and signalling. Thus modulation of SV biogenesis at the molecular level will allows future development of new targeted treatments for neurological diseases.
Inhibitory Signalling Switches Define The Machinery Of Synaptic Vesicle Endocytosis
Funder
National Health and Medical Research Council
Funding Amount
$387,489.00
Summary
The nerve cells in our brains are in constant communication to sustain life. Communication involves one nerve cell responding to electrical stimulation by releasing chemical messengers, from vesicles, onto the next cell. Our research focuses on the mechanism of recycling of vesicles. Targeting this mechanism is a way to gain fundamental knowledge of how to intervene medically when communication fails, or when communication needs to be dampened, in neurological diseases.
The Role Of Stargazin And TARP Phosphorylation In Synaptic Plasticity
Funder
National Health and Medical Research Council
Funding Amount
$423,305.00
Summary
A constant change in the strength of synaptic communication between neurons is critical for higher brain functions such as learning and memory. Synaptic strength is determined in part by the number of receptor ion channels at the synapse. This project will characterise how key interacting proteins regulate the synaptic targeting of these receptors in vivo. This research aims to understand the mechanisms of synaptic plasticity that may ultimately lead to new therapies for various brain disorders.
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
Mechanisms Of Synaptic Vesicle Endocytosis Revealed By Its Regulatory Phosphoproteome
Funder
National Health and Medical Research Council
Funding Amount
$545,216.00
Summary
The nerve cells in our brains are in constant communication to sustain life. Communication involves electrical stimulation of one nerve cell which then responds by releasing chemical messengers, from vesicles, onto the next cell. Our research focuses on the mechanism of recycling of vesicles. Targeting this mechanism is a way to gain fundamental knowledge of how to intervene medically when communication fails, or when communication needs to be dampened, such as in some neurological diseases.
Dynamin Inhibitors As Tools For Dissecting The Endocytic Pathway In Neurons
Funder
National Health and Medical Research Council
Funding Amount
$470,250.00
Summary
Nerve cells communicate by the release of neurotransmitters which are packaged in synaptic vesicles inside nerve endings. There is a finite number of vesicles, so they are recycled (endocytosis) for reuse. Some human neural diseases hijack the endocytic pathway for entry of pathological peptides, proteins or viruses to paralyse, kill or infect neurons. Our overall aim is to control nerve communication to ultimately allow us to treat disorders of nerve communication like epilepsy. At its most ext ....Nerve cells communicate by the release of neurotransmitters which are packaged in synaptic vesicles inside nerve endings. There is a finite number of vesicles, so they are recycled (endocytosis) for reuse. Some human neural diseases hijack the endocytic pathway for entry of pathological peptides, proteins or viruses to paralyse, kill or infect neurons. Our overall aim is to control nerve communication to ultimately allow us to treat disorders of nerve communication like epilepsy. At its most extreme, completely blocking endocytosis quickly results in a complete block in nerve communication. Therefore slowing it down (rather than blocking) might be a means to control some neural diseases. For example, a seizure is the uncontrolled firing of neurons. The main mechanisms controlling endocytosis converge on the protein dynamin. Dynamin can assemble into a tiny, tightly wound helix or spring. When energy (GTP hydrolysis) is applied to the nanospring it rapidly releases to cleave off empty recycling synaptic vesicles from the cell wall back into the neuron. Our premise is that blocking the nanospring may lead to a new generation of antiepileptic drugs. To achieve this we have already discovered the first chemical inhibitors of dynamin. In this project we will determine how they work, by showing that they target distinct sites in dynamin. We have embarked on an ambitious chemical synthesis program to greatly improve the potency and specificity of the inhibitors. We will expand this with an iterative approach using combinatorial chemistry. When applied to neurons, the drugs appear to be the first endocytosis inhibitors. Will test our proposal that they will reveal multiple points of action of dynamin in various stages of endocytosis. This project will prove the principle that the development of anti-dynamin drugs could lead to the first anti-endocytic drugs. This has the potential to lead to future development of targeted antiepileptic and anticancer drugs.Read moreRead less
Cholinergic Abnormalities In Alzheimer's Disease: Identification Of Novel Therapeutic Targets
Funder
National Health and Medical Research Council
Funding Amount
$478,500.00
Summary
The aim of this project is to develop new drugs for the treatment of Alzheimer's disease. Alzheimer's disease is a disease of ageing commonly associated with memory loss. The disease is caused by the build up of amyloid protein in the brain. However, it is not known how amyloid protein causes degeneration of normal brain function. Our previous studies have shown that amyloid protein targets two components which are important for normal brain function. These components are 1) acetylcholinesterase ....The aim of this project is to develop new drugs for the treatment of Alzheimer's disease. Alzheimer's disease is a disease of ageing commonly associated with memory loss. The disease is caused by the build up of amyloid protein in the brain. However, it is not known how amyloid protein causes degeneration of normal brain function. Our previous studies have shown that amyloid protein targets two components which are important for normal brain function. These components are 1) acetylcholinesterase and 2) nicotinic receptors, which are known to be important for memory. The aim of this application is to identify the mechanisms by which amyloid protein targets acetylcholinesterase and nicotinic receptors and to design inhibitors of this interaction which may ultimately provide a platform for future drug development.Read moreRead less
Mechanisms Of Glutamate Receptor Maturation In Chicken Brain
Funder
National Health and Medical Research Council
Funding Amount
$418,980.00
Summary
In the brain, many key proteins involved in signalling change during development as part of the fine tuning of the network of connections between nerve cells. Disorders of this fine tuning are thought to result in a number of neurological or psychiatric conditions such as epilepsy and schizophrenia. This project will investigate the maturation of signalling molecules in the brain (receptors for the neurotransmitter glutamate, key enzymes called protein kinases and protein phosphatases that contr ....In the brain, many key proteins involved in signalling change during development as part of the fine tuning of the network of connections between nerve cells. Disorders of this fine tuning are thought to result in a number of neurological or psychiatric conditions such as epilepsy and schizophrenia. This project will investigate the maturation of signalling molecules in the brain (receptors for the neurotransmitter glutamate, key enzymes called protein kinases and protein phosphatases that control the activity of receptors and scaffolding proteins that bind the whole lot into a signalling complex). The project uses chickens as a novel animal model because chicken brain has a slow maturation that occurs well after the initial wiring of the brain is complete. This enables the maturation changes to be clearly identified and experimentally modified. The project combines investigations at the molecular, physiological and behavioural levels. The effects of hormones and drugs on maturation will be investigated. Because brain maturation in humans is also slow an understanding of the way in which this maturation is controlled may provide insights into what causes some neurological-psychiatric disorders in children and adolescents and how to treat or prevent them.Read moreRead less