Nerve cells have unique properties like their ability to put out axons that reach long distances from the cell body (differentiation), their ability to make contacts with other cells and initiate communication by the release of neurotransmitters from synaptic vesicles inside nerve endings (exocytosis) and the recycling of those synaptic vesicles (endocytosis). These events are mainly controlled by a large number of synapse-specific proteins, and partly regulated by a signalling molecule, cGMP, w ....Nerve cells have unique properties like their ability to put out axons that reach long distances from the cell body (differentiation), their ability to make contacts with other cells and initiate communication by the release of neurotransmitters from synaptic vesicles inside nerve endings (exocytosis) and the recycling of those synaptic vesicles (endocytosis). These events are mainly controlled by a large number of synapse-specific proteins, and partly regulated by a signalling molecule, cGMP, which mainly stimulates the enzyme PKG. In previous studies supported by the NHMRC we identified many proteins that are phosphorylated and activated by PKG. One of them, septin 3, is the focus of this proposal. We initially cloned septin 3 as a new member of a family of 10 genes that are essential for cell division. Some septins assemble as filaments that allow the two new daughter cells to finally separate. When the filament formation is perturbed certain septins end up in microscopic clumps that are found in the post-mortem brains of people affected by Alzheimer's disease, suggesting they might contribute to the disease. However, septin 3 is unlike most septins because it is a brain-specific septin, which we found in neurons and found to be highly concentrated in nerve terminals, locations not normally associated with cell division. The only other known brain-specific septin, CDCrel-1, regulates the protein machinery of exocytosis. We will examine the hypothesis that G-septin is also a regulator of synaptic vesicle endocytosis. We will determine whether septin represents a convergence point for cGMP signalling to control endocytosis. A better understanding of septin 3 and endocytosis is crucial to understanding brain disorders and ultimately developing better therapies.Read moreRead less
The Function Of Dynamin Phosphorylation Sites In Synaptic Vesicle Endocytosis
Funder
National Health and Medical Research Council
Funding Amount
$794,565.00
Summary
Neurons communicate with each other via the release of neurotransmitters which are packaged in synaptic vesicles inside nerve endings. There are a finite number of vesicles, so they are recycled (endocytosis) for reuse. Synaptic vesicle exocytosis is very fast and normally endocytosis is a little slower, mopping up the used vesicles. Recently we showed that endocytosis can control synaptic transmission, hence it's an integral part of an overall cycle of synaptic transmission. We found that when ....Neurons communicate with each other via the release of neurotransmitters which are packaged in synaptic vesicles inside nerve endings. There are a finite number of vesicles, so they are recycled (endocytosis) for reuse. Synaptic vesicle exocytosis is very fast and normally endocytosis is a little slower, mopping up the used vesicles. Recently we showed that endocytosis can control synaptic transmission, hence it's an integral part of an overall cycle of synaptic transmission. We found that when endocytosis cannot keep up then exocytosis slows, greatly reducing the function of neurons. A complete block would result in paralysis of brain and muscles. Our team has been revealing the underlying molecular mechanisms of endocytosis in order to better understand diseases of the synapse like schizophrenia, epilepsy and Alzheimer's disease. We discovered that endocytosis is a regulated process at the heart of which is a pair of phosphorylation sites (points of phosphate attachment) in the key protein dynamin I. Our hypothesis is that endocytosis occurs in two forms, fast and slow. We propose to test the idea that proteins that associate with dynamin via the phosphorylation sites determine whether the fast or slow mode is used. Additionally, we propose that the first phosphorylation site is the trigger for endocytosis, while the second serves to recruit reserve supplies of dynamin to support the slow mode when it's required. A better understanding of Dyn and endocytosis is crucial to understanding brain disorders of synaptic transmission and ultimately for developing therapies. For example, a seizure is the uncontrolled firing of neurons. Our overall aim is to understand the control mechanisms of nerve communication to ultimately allow us to treat disorders of nerve communication like epilepsy.Read moreRead less
Role Of Dynamin In Modes Of Synaptic Vesicle Endocytosis
Funder
National Health and Medical Research Council
Funding Amount
$905,985.00
Summary
Neurons communicate by neurotransmitter release from synaptic vesicles stored in nerve endings. There is a finite vesicle number, so they are recycled (endocytosis) by dynamin. Our aim is to reveal the molecular mechanisms underlying endocytosis to better understand diseases of the synapse like epilepsy. We propose that two forms of the dynamin gene mediate two forms of endocytosis, one of which is activated only under conditions of high neuronal firing, such as occurs during a seizure.