Diseases of neurotransmission
The synapse is centre stage for many brain diseases. Many disease related genes have been identified that code for proteins involved in neurotransmitter release, synapse morphology and synaptic plasticity. A major focus of the Synapse Proteomics Group is the synaptic vesicle cycle proteins involved in disease.
Endocytosis in neurotransmission
Endocytosis is a fundamental process that occurs in all eukaryotic cells. Defects in endocytosis limit the ability of a cell to internalise molecules and properly respond to environmental queues. Defects in endocytosis also affect exocytosis and intracellular trafficking because these processes are reliant on the proper sorting of the exocytic machinery during endocytosis. This is particularly important in the brain where cyclic exocytosis and endocytosis is required to maintain neurotransmission.
The most well understood mode of endocytosis is clathrin-mediated endocytosis (CME). CME involves the formation of a lattice-like clathrin coat over the budding vesicle. Clathrin assembly proteins are responsible for making vesicles of a consistent size and shape. We are focused on defining the molecular mechanism of events during assembly of the clathrin coat, including the signalling events mediated by post-translational modifications.
A better understanding of neurotransmission will help us determine what goes wrong in a range of diseases like epilepsy, autism and Alzheimer’s disease. It also tells us about normal learning and memory.
AP180 and CALM are a major focus of our group. Both are clathrin assembly proteins. AP180 is only found in brain and forms small vesicles in the synapses of neurons. The mechanism of clathrin assembly by AP180 is not yet well understood. The gene for AP180 has been implicated in bipolar disorder.
CALM is found in all cells of the body where it is involved in receptor internalisation which has implications for both Alzheimer’s and leukaemia. The fusion of CALM and AF10 via chromosomal translocation causes an acute leukaemia. A better understanding of CALM function may lead to therapeutics that can better target and potentially prevent the aberrant functions of this fusion product.
Polymorphisms in the gene for CALM have been found in Alzheimer’s patients. CALM may have a role the clearance of amyloid plaques or the processing of amyloid precursor protein (APP). CALM is known to be involved in APP-trafficking, so it could contribute to Alzheimer’s by trafficking APP to where it can break down and eventually form plaques. Understanding how CALM works will allow us to achieve the ultimate goal of finding subtle ways to regulate endocytosis and modulate its function to treat these diseases.
Follow the phosphate
Post-translational modification, which is the addition of molecules to a protein after it has been made, often significantly changes protein function. Therefore, rather than directly targeting a disease-related protein with a drug, it is possible to change protein function by targeting the enzymes involved in protein post-translational modification. We study protein phosphorylation, since it is the most common post-translational modification. We measure changes to the level of phosphate on both individual proteins and sometimes thousands of proteins at once to determine normal phosphorylation signalling that occurs presynaptically during neurotransmission. Phospho-signalling directed at disease-related proteins is picked up in these screens. The phospho-signalling pathways can potentially be exploited as a targeted way to treat disease.
We have identified novel activity-dependent signalling to proteins involved in Alzheimer’s disease, autism and epilepsy. Our signalling network data also fills in a major gap in our fundamental knowledge of presynaptic neurotransmission and this is where we aim to add significantly to global efforts to model brain function.