Defining A Role For The STONED Proteins In The Synaptic Vesicle Cycle
Funder
National Health and Medical Research Council
Funding Amount
$301,527.00
Summary
Nerve cells communicate with each other by means of chemical neurotransmitters. The level of communication is strictly controlled, and changes in the level, either up or down, is known as synaptic plasticity. This plasticity is thought to underly changes in the brain that account for both long and short term memory. Uncontrolled alterations in plasticity can also induce abnormal brain function, resulting in neurological disorders. Changes in the release of neurotransmitter are regulated at the m ....Nerve cells communicate with each other by means of chemical neurotransmitters. The level of communication is strictly controlled, and changes in the level, either up or down, is known as synaptic plasticity. This plasticity is thought to underly changes in the brain that account for both long and short term memory. Uncontrolled alterations in plasticity can also induce abnormal brain function, resulting in neurological disorders. Changes in the release of neurotransmitter are regulated at the molecular level by unknown mechanisms, however the chemical neurotransmitters are enclosed in small vesicles and it is believed that the control of the release of these vesicles, and their recycling, are important components of this mechanism. We have identified a gene that encodes two novel proteins of neurotransmission. Mutations that alter these genes can result in either increased or decreased synaptic activity. By using a combination of genetic and molecular techniques we propose to investigate how one of these two proteins operate to alter synaptic activity, as well as attempting to show how it interacts with other components of the synaptic machinery.Read moreRead less
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
Sulfonadyn-based Dynamin I-specific Inhibitors And Epilepsy
Funder
National Health and Medical Research Council
Funding Amount
$835,291.00
Summary
Epilepsy affects 1% of people, yet 30% do not respond to anti-epileptic drugs (AEDs). Traditional drug discovery fails to improve this situation. Our team discovered dynamin as a new target for better AED design and our lead sulphonadyns reduces seizures in animals. We will design better sulfonadyns that can ultimately be used for clinical trials by designing the drugs away from its actions outside of neurons. If successful, this will accelerate new AED development with less side-effects.
The Molecular Mechanisms Of Abscission To Complete Cytokinesis
Funder
National Health and Medical Research Council
Funding Amount
$736,337.00
Summary
Cytokinesis is the final stage of cell division that produces two daughter cells. Incorrect localisation and modification of proteins that regulate this process cause cell division errors potentially leading to cancer. This project will characterise how key cytokinesis proteins function co-operatively to complete cytokinesis. This research will increase our understanding of the cell division errors that contribute to cancer development, ultimately identifying new targets for cancer therapy.
Development Of Dynamin Inhibitors As Novel Therapies For Epilepsy
Funder
National Health and Medical Research Council
Funding Amount
$903,376.00
Summary
Epilepsy affects 1% of people, but 30% do not respond to current anti-epileptic drugs (AEDs). Traditional drug discovery has not improved this situation. Our team discovered two exciting new targets for design of better AEDs. One of them blocks seizure in animals. Our aim is to determine how well they work in true animal models of epilepsy. If successful, this will accelerate development of new AEDs with less side-effects, benefiting large sectors of the Australian community.
Consequences Of Dynamin 2 PH Domain Dysfunction In Charcot-Marie-Tooth Neuropathy
Funder
National Health and Medical Research Council
Funding Amount
$665,267.00
Summary
Our team has just discovered a new gene mutation that causes Charcot-Marie-Tooth (CMT) disease. CMT is a clinically and genetically diverse family of human peripheral neuropathies. CMT neuropathy is the most common inherited peripheral neuropathy, affecting approximately 1 in 2500. It is the most common human genetic disorder known and is caused by fifty or more genes. CMT is of large economic significance since many of the affected individuals are on lifetime invalid pensions and require contin ....Our team has just discovered a new gene mutation that causes Charcot-Marie-Tooth (CMT) disease. CMT is a clinically and genetically diverse family of human peripheral neuropathies. CMT neuropathy is the most common inherited peripheral neuropathy, affecting approximately 1 in 2500. It is the most common human genetic disorder known and is caused by fifty or more genes. CMT is of large economic significance since many of the affected individuals are on lifetime invalid pensions and require continual medical and paramedical support. The new mutation we discovered is in a variant form of CMT and affects the protein dynamin 2, in an important region called the PH domain. The normal function of Dyn2 is to retrieve activated receptors for hormones and growth factors from the membrane of cells (caller receptor mediated endocytosis or RME) and it is also required for other functions like cell proliferation. The PH domain is the part of Dyn2 that allows it to move to the appropriate part of the cell when needed to do its job, but it is not known whether the mutation disrupts this function of Dyn2. Since Dyn2 has multiple cellular functions, it is not understood why it might cause the disease. Our goal is to understand why this mutation causes peripheral nerves to degenerate, by revealing which of dynamin's many functions are primarily affected. We expect to uncover a new concept in how RME links to neuronal degeneration. In previous studies we developed the first drugs that interact with PH domains. We will now fully develop these, and synthesise new drugs that interact with the PH domain, as candidates to effect some repair of the damaged PH domain. A better understanding of Dyn2 and endocytosis is crucial to understanding both CMT and ultimately for developing therapies.Read moreRead less