New class of proteins can help treat neurological diseases

At the University of Texas Health Science Center at San Antonio (UT Health San Antonio), scientists have identified a new group of proteins that guard synapses against damage.

Gek-Ming Sia, PhD. Image Credit: University of Texas Health Science Center at San Antonio.

Synapses are essentially the structures in which electrical impulses travel from one neuron to another.

The latest finding, published in the Nature Neuroscience journal on July 13^th, 2020, holds implications for schizophrenia and Alzheimer’s disease. If this is discovery is proven, boosting the number of such protective proteins could result in an innovative therapy for controlling those diseases, stated the scientists.

In the case of schizophrenia, loss of synapses at the time of development predisposes a person to this disorder. In the case of Alzheimer’s disease, synapse losses result in various clinical symptoms, including memory problems.

We are studying an immune system pathway in the brain that is responsible for eliminating excess synapses; this is called the complement system.”

Gek-Ming Sia, PhD, Study Senior Author and Assistant Professor, Department of Pharmacology, University of Texas Health Science Center at San Antonio

Dr Sia continued, “Complement system proteins are deposited onto synapses. They act as signals that invite immune cells called macrophages to come and eat excess synapses during development. We discovered proteins that inhibit this function and essentially act as ‘don’t eat me’ signals to protect synapses from elimination.”

The system sometimes goes awry

Synapses are overproduced during development. Humans are known to have the most numbers of synapses between the ages of 12 and 16. Then, from around the age of 20, there is net elimination of synapses that is a usual part of the brain’s maturation process. Such a process needs the complement system.

The numbers of synapses are stable in the case of adults because the elimination and formation of synapses balance out. However, in specific neurological disorders, the brain is somehow damaged and starts to overproduce complement proteins, which result in excess loss of synapses.

According to Dr Sia, “This occurs most notably in Alzheimer’s disease.”

In Alzheimer’s disease mouse models, scientists have discovered that when complement proteins are removed from the brain, the latter is protected from neurodegeneration, Dr Sia added.

We’ve known about the complement proteins, but there was no data to show that there were actually any complement inhibitors in the brain. We discovered for the first time that there are, that they affect complement activation in the brain, and that they protect synapses against complement activation.”

Gek-Ming Sia, PhD, Study Senior Author and Assistant Professor, Department of Pharmacology, University of Texas Health Science Center at San Antonio

Future direction

Along with his collaborators, Dr Sia will seek to answer some important questions:

• How the number of complement inhibitors can be modified and whether that might have clinical ramifications?
• Whether complement system biology can describe why certain individuals are more resilient and more resistant against specific psychiatric disorders?
• Whether different types of neurons create different complement inhibitors, each guarding a specific subset of synapses?

With regard to the last question, Dr Sia noted, “This could explain why, in certain diseases, there is preferential loss of certain synapses. It could also explain why some people are more susceptible to synapse loss because they have lower levels of certain complement inhibitors.”

The scientists targeted a neuronal complement inhibitor known as SRPX2. The studies are being performed in mice in which the SRPX2 gene is absent, demonstrating the overactivation of the complement system and exhibiting the excess loss of synapses.