Scientists at The University of Texas Medical Branch at Galveston have unraveled how certain proteins work together to regulate the formation of connections between neurons.
The human brain contains an estimated 100 billion neurons and these neurons communicate with each other through hundreds of trillions of synapses, the contact and communication points between connected neurons.
“Your ability to think, feel happy, feel sad, decide to eat or not, and so forth, all lies encoded within neural circuits in your brain,” said Gabby Rudenko, associate professor in the UTMB department of pharmacology and toxicology, and Sealy Center for Structural Biology and Molecular Biophysics. “However, neural circuits, and specifically the synapses that connect neurons into specific circuits, can also be altered contributing to the development of neuropsychiatric diseases like autism spectrum disorder and schizophrenia.”
In a study published in the journal Neuron, Rudenko and other researchers at UTMB focused on proteins that reach out across the cleft between two neurons connected at a synapse and make trans-synaptic bridges.
“There are hundreds if not thousands of proteins, if you consider all forms of each protein, that facilitate synaptic connections and, while some have been studied, there are many more that we don’t know much about,” Rudenko said.
The traditional school of thought has been that one protein from each side of the synaptic cleft combine to form a trans-synaptic bridge that helps form and/or stabilize a synapse connecting two neurons.
However, UTMB researchers found that a third molecule can block this connection by getting in between the two proteins.
By determining their three-dimensional structures, Rudenko and her colleagues revealed how trans-synaptic bridges formed by the proteins neuroligins and neurexins can be blocked by a third competing protein known as MDGA, regulating the synapse development.
“Understanding these synaptic connections is critically important because neurexins, neuroligins and MDGAs are all implicated in severe neuropsychiatric disorders,” Rudenko said. “This kind of scientific work is difficult because it requires top-notch facilities for structural biology like we have at the Sealy Center for Structural Biology in order to build upon a wealth of amazing research conducted by neuroscientists at places like UTMB and actually at universities all over the world. Not many places outside of universities like UTMB are willing to provide the space and the resources needed to carry out the kind of study we have just completed.”
But it is critically important work that can hopefully have an impact on designing new treatments for neurological diseases.
“There is a huge amount of interest in knowing how proteins at synapses work, how these connections are made and how lesioned or damaged proteins at synapses contribute to neuropsychiatric disorders in people,” Rudenko said. “It is like a Lego set with many kinds of building blocks and we want to figure out how the right pieces snap together in order to form the right connections between brain cells and make sure those connections stay formed, or get eliminated if you need them to be.”
Other authors include Shanti Pal Gangwar, Xiaoying Zhong, Suchithra Seshadrinathan, Hui Chen and Mischa Machius.
This research was funded by the National Institute of Mental Health, the UT BRAIN Award, the Brain and Behavior Research Foundation and the Sealy Center for Structural Biology and Molecular Biophysics at UTMB.
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