SCIENTISTS at Trinity College Dublin have discovered how two proteins interact to guide connections between brain cells.
The proteins were known to be involved in brain wiring, and the Trinity and Oxford study has now identified how they bind in order to tell brain cells to avoid connecting with each other. Understanding how brain cells make connections is important, according to one of the study’s authors, Dr Kevin Mitchell, a senior lecturer at the Smurfit Institute of Genetics and the Institute of Neuroscience at TCD. “The brain may have thousands of different regions that have different functions, and they have to be wired up together in a very specific way,” he said.
“If genes that specify how nerves connect up to each other are mutated you can end up with conditions like schizophrenia, autism or epilepsy.
"So by trying to understand the normal processes , and what happens when they go wrong, the hope is we can get to a point where we understand those disorders at a detailed biological level." The new study, published in the scientific journal Nature, looked at a "semaphorin" protein, known as Sema6A, which has a role in putting the brakes on brain cell connections and stopping excessive nerve growth.
The research, for which the Trinity team received funding from Science Foundation Ireland, examined the interaction between Sema6A and another protein, PlexinA2. The proteins both stick out of brain cells like antennae, and when Sema6A on one cell binds with PlexinA2 on another, it tells the cells to avoid each other.
“While the proteins stick to each other, they don’t actually make the cells stick to each other; it induces a signal that [tells] the cells to repel each other,” Dr Mitchell said.
“We knew these proteins bound to each other but we didn’t know the detail of how they did that.”
The collaboration between Trinity and Oxford used X-ray diffraction crystallography to identify specific regions in the three-dimensional structures of the proteins that fit together to interact. “Now we know the exact details of how that interaction occurs at the atomic level,” said Dr Mitchell.
“We could also test which of those atomic interactions was most crucial for the binding of the two proteins and for initiating the response in each cell.” He added that understanding how the two proteins fit together could lead to new ways to block the interaction.
Developing a way to block the signal from Sema6A could potentially help encourage nerve cells to grow when needed, such as after spinal cord injury, added Dr Mitchell – though he stressed that was far into the future.
