Children’s Medical Research Institute’s Cell Signalling team has made the front cover of the EMBO Journal for a discovery that they hope will open up a path towards targeted therapies for epilepsy.
The work was led by Professor Phil Robinson, Head of CMRI’s Cell Signalling Unit, and included team members Jing Xue and George Craft and a former PhD student Lin Luo.
Prof Robinson’s team study how signals are sent from one cell to another in the body, with a focus on developing new treatments for epilepsy. He has described this work as the “clearest and most satisfying part of my career to date’’.
Communication between neurons in the brain requires a step where electrical signals travelling along a nerve are converted into chemical signals that travel between small gaps between the neurons. This gap is called the synapse, and synaptic transmission, the process by which signals travel this gap, is an important area of research for understanding everything from learning and memory to diseases such as epilepsy.
A fundamental part of synaptic transmission is a process called endocytosis which allows the neurotransmitters to be recycled between signalling events to allow for continuous nerve function. Prof Robinson’s team were the first to identify some of the key players in this process, and their work on Dynamin has led to the discovery of a whole new category of drugs that can treat a range of diseases.
Their latest work focuses on Dynamin 1, a neuron-enriched form of the classical dynamins, which has two major variants, Dyn1xA and xB, both found in neurons in about equal abundance but xA has a slightly longer tail. The team used advanced biochemical and time-resolved electron microscopy to understand for the first time how Dyn1xA works and why only this longer form is crucial for ultrafast endocytosis—which is complete in less than 100 milliseconds and is vital for brain function.
“This was an extraordinary surprise,’’ Prof Robinson said. “We couldn’t work out previously how this was all possible. This is a fundamental basic science discovery– to understand a new principle underlying how nerves work.’’
Prof Robinson said the implication of this is that this information “opens up a whole range of new ideas on how to one day make a drug that will be far better for epilepsy’.
“Current drugs for epilepsy reduce the function of the nerves but have side effects because they are untargeted,’’ he said.
“We are trying to get a better epilepsy drug, and this discovery will allow us to only block the neurons underlying that seizure spread and not block cell endocytosis function in the whole body.’’
He paid tribute to his CMRI team and collaborators at the John Hopkins University in Baltimore in the US who made it all possible by working together for the last 4 years.
“This couldn’t have happened without the long-term vision of our team and the incredible talent of our network of collaborators. It really is a marriage made in heaven.’’
Read full article here: https://www.embopress.org/doi/full/10.1038/s44318-024-00145-x