Protein partners and neural transmission

Of the multitude of proteins identified within the cells of the brain, no one has ever been quite sure of the role played by syndapin. We know it's there within the neuron but we have never been certain about what it gets up to.

Now, researchers led by Dr Phil Robinson and PhD student Victor Anggono at Sydney's Children's Medical Research Institute (CMRI) Cell Signalling Unit, in association with the University of Edinburgh, have identified that syndapin plays an essential role in synaptic vesicle endocytosis (SVE), the retrieval of the empty synapse after the release of neurotransmitter. The team has discovered that syndapin binds with the protein dynamin and is at the heart of the machinery of the synapse.

Robinson said the team had made a major breakthrough that will allow it to target the process following exocytosis, rather than concentrating on what happens before, thus opening up new ways of treating synaptic diseases such as epilepsy and possibly schizophrenia and some mood disorders.

The discovery of the function of this protein should not be underrated, Robinson said. "What we have done is made a fundamental breakthrough in medical science. We know more about how the brain works as a result."

The neuron contains hundreds of synapses, and within these are hundreds of small synaptic vesicles. Synaptic vesicles are fundamentally a package of neurotransmitter, which is released across the synapse to the next neuron. The neurons talk to each other, sending thoughts, laying down memory and controlling nerve function.

In synaptic transmission, the vesicle 'fuses', diving into the wall of the synapse and releasing the neurotransmitter onto the next cell, a process called exocytosis. The vesicle is then retrieved and refilled with neurotransmitter, known as endocytosis. It was known that the dynamin protein makes a 'collar' around the vesicle during endocytosis, but the breakthrough finding is that to do so, dynamin needs a partner. That partner is syndapin.

"The empty vesicle is what we are studying," Robinson said. "It has no content, no neurotransmitter. If that synaptic vesicle is not retrieved and is not re-filled, then synaptic transmission stops. And that's the process that we are looking at."

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Synaptic transmission

Robinson said the importance of the find is two-fold: it is a fundamental discovery in the understanding of how neurons work and it promises some exciting medical applications in the future.

"By blocking the dynamin-syndapin interaction, we are able to block synaptic transmission," he said. "In normal circumstances you don't want to do that as you end up with paralysis, which is not a good thing in the brain. However, in this case the way that we block synaptic transmission is very different. We block it in an activity-dependent manner - we block it slowly over time."

In conditions such as epilepsy, which involves the overactive firing of neurotransmitters, the discovery could have huge ramifications, he said. "Epilepsy starts at a focal point in the brain and by neurons firing and continuing to fire the seizure spreads. We believe that by blocking the interaction between dynamin and syndapin we can stop the spread of that seizure because the neurons that are overactive won't be able to sustain it."

He said drugs to control epilepsy currently target the process of exocytosis but he and his team are looking at endocytosis instead. "Anti-epileptic drugs target proteins that are upstream of the synaptic transmission event but they depress the brain - they change your mood, they change your behaviour. Our idea is downstream - the source of the fresh vesicles.

"I don't think that dynamin drugs will not affect the brain - they will have a different range of side-effects - but they will have the same outcome: blocking the seizure."

A second application could lie in new treatments for schizophrenia, bipolar disorder and depression, he said. "We think there's a strong possibility that this machinery is important in diseases of the synapse, which include schizophrenia. These are diseases of synaptic transmission, diseases of the pre-synaptic terminal, which we believe are caused by over-activity of the synapse. We believe it but can't yet prove it."

The primary discovery of the role of syndapin was made by Anggono three years ago but it has taken that time to find the evidence and have the work published in the 28 May issue of Nature Neuroscience.

The team at the CRMI's Cell Signalling Unit also included Val Valova and Mark Graham, who did the hard yards on the mass spectrometer (two of which, a MALDI and a tandem mass spec from Applied Biosystems, were purchased using funds from the institute's Jeans for Genes campaign). The Sydney team worked closely on the discovery with two colleagues from the University of Edinburgh, Michael Cousin and Karen Smillie.

25-year-old Anggono, who is doing his PhD at the University of Sydney, was recently awarded a fellowship from the Australian Society for Biochemistry and Molecular Biology for his work, which he says will allow him to do further study overseas.

Another of Anggono's discoveries, that syndapin is not present in non-neuronal cells, holds out great potential for further and wider research, Robinson said.