UT Southwestern researchers pinpoint role cell surface protein group plays in brain function

A specific group of brain proteins is essential to activate communication between neurons, and without this group of proteins all functions of the central nervous system are disrupted, researchers at UT Southwestern Medical Center at Dallas have discovered.

The disruption of this specialized group of proteins, called alpha-Neurexins, causes severe interruption of synaptic transmission, which is essential for neurons to communicate in the central nervous system. Synapses are specialized junctions where neurons communicate with target cells.

The study findings, which were discovered in mice and published in today’s issue of Nature, expand the knowledge of the process of synaptic transmission and gives scientists new insight into how the brain works. Gaining a fundamental understanding of brain function is critical in order to eventually counter the degenerative effects of neurological diseases such as Alzheimer’s and Parkinson’s diseases and schizophrenia, said Dr. Thomas Südhof, director of both the Center for Basic Neuroscience and the C. Vincent Prothro Center for Research in Basic Neuroscience at UT Southwestern and the study’s senior author.

“If you want to have any type of insight on how the brain works
you need to understand synaptic transmission,” he said.

“The results from this study were a big surprise,” Dr. Südhof said. “When we originally described alpha-Neurexin almost 10 years ago, we hypothesized that the proteins would be involved in signaling the synapses. We thought of it more in terms of the formation of the synapses. The surprise is that it turns out not to be involved in the formation of synapses but what happens subsequently to activate synapses.”

To identify the role of these proteins, the researchers used genetically engineered laboratory mice that lacked alpha-Neurexin. The absence of the proteins in the mice resulted in the inactivity of the presynaptic half of the synapses, which is responsible for sending messages to neurons.

This led to an interruption of the mice’s breathing and ultimately death. After examining the nervous system of the mice, the researchers surprisingly found that all components of the nervous system were interrupted.

“The absence of alpha-Neurexin not only interferes with breathing, but it also disrupts all others functions of the nervous system, including perception and motor capabilities,” said Dr. Südhof, who holds the Gill Distinguished Chair in Neuroscience Research and the Loyd B. Sands Distinguished Chair in Neuroscience.

Dr. Südhof and his collaborators began the current study almost eight years ago.

“Solving such fundamental questions is paramount in understanding any disease, especially neuronal diseases,” said Dr. Südhof, who is also an investigator in the Howard Hughes Medical Institute at UT Southwestern and a member of the National Academy of Sciences.

“I think that the experiences of the last decade or so tell us that any neurological disease that affects the brain requires an understanding of the fundamental mechanisms. You can’t just look at the specific disease. At the most fundamental level, the brain functions by synaptic transmission and this process must be understood first in order to understand neurological diseases.”

Other researchers involved in the study include Dr. Robert Hammer, a professor of biochemistry at UT Southwestern; researchers from the Center for Basic Neuroscience at UT Southwestern; and German researchers from Georgia Augusta University in Göttingen and Ruhr University in Buchum.

The study was funded by the National Institutes of Health and the Deutsche Forschungsgemeinschaft.