Molecular Neuroscience Laboratory
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Research

The Molecular Neuroscience lab studies the developmental mechanisms through which neuromuscular synapses form, the physiological processes by which they are modified in adult life (synaptic plasticity) and degenerative changes to the synapse that occur in neuromuscular diseases.

Motor nerves from the spinal cord control our voluntary muscles via a connection called the neuromuscular synapse. At this synapse the end of the nerve forms branches that are closely associated with the surface of the muscle fibre. The branches are specialized, to release the chemical, acetylcholine, when impulses come down the nerve. This triggers muscle contraction via the acetylcholine receptor.
↑ neuromuscular synapse viewed from above stained with an antibody to reveal a protein in the nerve terminal called syntaxin. Syntaxin prepares acetylcholine to be released. The nerve (from the spinal cord) enters the picture from the lower left.

Beneath the nerve terminal branches the surface of the muscle cell is also specialised. This is called the postsynaptic membrane. Receptors for acetylcholine are aligned beneath each acetylcholine release site to respond to its chemical signal.
↑ a protein called rapsyn binds to the acetylcholine receptor proteins (AChR) pulling them together in the postsynaptic membrane. Rapsyn, tagged with jellyfish green fluorescent protein, can be used to study the targeting of rapsyn and AChR to the postsynaptic membrane (image above). More info...

Molecules behind diseases of the neuromuscular synapse
The neuromuscular synapse becomes impaired or completely lost in a variety of disorders. For example, in myasthenia gravis, dysfunction of the immune system can produce antibodies that attach to, and interfere with, the AChRs. The muscle then becomes unresponsive to acetylcholine, leading to serious muscle weakness and fatigue. More info...

Our recent work has shown that some cases of myasthenia gravis can be caused by the patient’s own antibodies against another synaptic signaling protein, called Muscle Specific Kinase (MuSK). The antibodies interfere with the signalling function of MuSK. When injected into mice they cause the synapse to begin to come apart. This work has provided an explanation for the severe weakness experienced by these patients.

The fluorescence microscopic image at left shows healthy neuromuscular synapses with clusters of postsynaptic acetylcholine receptors (red fluorescent labeling) contacted by nerve terminals (green fluorescence). In mice injected with patient anti-MuSK IgG (right hand panel), acetylcholine receptor staining became dim and nerves were displaced from the postsynaptic acetylcholine receptor clusters. For the full story on this click here.

The agrin-MuSK system- what does it do?
MuSK is part of the agrin-MUSK system of signaling between nerve and muscle. Most of what we know about the agrin-MuSK system comes from studies at the embryonic stages of life when synapses are first forming. At this early stage of life both agrin and MuSK are essential. Agrin, a protein molecule released by the nerve ending, signals through MuSK to stabilize embryonic synapses. Click here for a brief review.

It is now becoming evident that mature neuromuscular synapses may also need this agrin-MuSK system to survive. We need to learn more about such natural regulatory systems if we are to understand, and perhaps delay, the loss of synapses that contributes to weakness in other neuromuscular disorders and during normal aging.

Fortunately the tools of molecular and cell biology, combined with physiology now make it possible to investigate the natural homeostatic mechanisms involving agrin-MuSK and other signalling systems that keep the neuromuscular synapse healthy. It is by learning more about these protective mechanisms that we will be better positioned to understand synapse loss and how we might prevent it.

If you would like to learn more about the Molecular Neuroscience laboratory and its research projects please contact Bill Phillips (lab head)
Email : william.phillips@sydney.edu.au
Phone : +61 2 9351 4598
Fax : +61 2 9351 2058
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