Synapse-Saving Proteins Discovered, Opening Possibilities in Alzheimer’s and Schizophrenia

Summary: Study identified a new class of proteins that protect synapses from being destroyed. The findings have important implications for both Alzheimer’s disease and schizophrenia.

Source: UT San Antonio

Researchers at The University of Texas Health Science Center at San Antonio (UT Health San Antonio) have discovered a new class of proteins that protect synapses from being destroyed. Synapses are the structures where electrical impulses pass from one neuron to another.

The discovery, published July 13 in the journal Nature Neuroscience, has implications for Alzheimer’s disease and schizophrenia. If proven, increasing the number of these protective proteins could be a novel therapy for the management of those diseases, researchers said.

In Alzheimer’s disease, loss of synapses leads to memory problems and other clinical symptoms. In schizophrenia, synapse losses during development predispose an individual to the disorder.

“We are studying an immune system pathway in the brain that is responsible for eliminating excess synapses; this is called the complement system,” said Gek-Ming Sia, PhD, assistant professor of pharmacology in UT Health San Antonio’s Long School of Medicine and senior author of the research.

“Complement system proteins are deposited onto synapses,” Dr. Sia explained. “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

During development, synapses are overproduced. Humans have the most synapses at the ages of 12 to 16, and from then to about age 20, there is net synapse elimination that is a normal part of the brain’s maturation. This process requires the complement system.

In adults, synapse numbers are stable, as synapse elimination and formation balance out. But in certain neurological diseases, the brain somehow is injured and begins to overproduce complement proteins, which leads to excessive synapse loss.

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

In mouse models of Alzheimer’s disease, researchers have found that the removal of complement proteins from the brain protects it from neurodegeneration, he said.

“We’ve known about the complement proteins, but there was no data to show that there were actually any complement inhibitors in the brain,” Dr. Sia said. “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.”

Future directions

Dr. Sia and his colleagues will seek to answer interesting questions, including:

  • Whether complement system biology can explain why some people are more resistant and more resilient against certain psychiatric disorders;
  • How the number of complement inhibitors can be changed and whether that could have clinical ramifications;
  • Whether different neurons produce different complement inhibitors, each protecting a certain subset of synapses.

Regarding the last question, Dr. Sia said:

“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.”

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This shows a brain made up of network nodes
In Alzheimer’s disease, loss of synapses leads to memory problems and other clinical symptoms. In schizophrenia, synapse losses during development predispose an individual to the disorder. Image is credited to UT San Antonio.

The researchers focused on a neuronal complement inhibitor called SRPX2. The studies are being conducted in mice that lack the SRPX2 gene, that demonstrate complement system overactivation and that exhibit excessive synapse loss.

Funding: This project is funded by a NARSAD Young Investigator Award from the Brain and Behavior Research Foundation, a grant from the William and Ella Owens Medical Research Foundation, a Rising STARs Award from The University of Texas System, and grants from two branches of the U.S. National Institutes of Health – the National Institute of Neurological Disorders and Stroke, and the National Institute on Deafness and Other Communication Disorders.

About this neuroscience research article

Source:
UT San Antonio
Media Contacts:
Will Sansom – UT San Antonio
Image Source:
The image is credited to UT San Antonia.

Original Research: Open access
“The endogenous neuronal complement inhibitor SRPX2 protects against complement-mediated synapse elimination during development”. by Qifei Cong, Breeanne M. Soteros, Mackenna Wollet, Jun Hee Kim and Gek-Ming Sia. Nature Neuroscience


Abstract

The endogenous neuronal complement inhibitor SRPX2 protects against complement-mediated synapse elimination during developments

Complement-mediated synapse elimination has emerged as an important process in both brain development and neurological diseases, but whether neurons express complement inhibitors that protect synapses against complement-mediated synapse elimination remains unknown. Here, we show that the sushi domain protein SRPX2 is a neuronally expressed complement inhibitor that regulates complement-dependent synapse elimination. SRPX2 directly binds to C1q and blocks its activity, and SRPX2−/Y mice show increased C3 deposition and microglial synapse engulfment. They also show a transient decrease in synapse numbers and increase in retinogeniculate axon segregation in the lateral geniculate nucleus. In the somatosensory cortex, SRPX2−/Y mice show decreased thalamocortical synapse numbers and increased spine pruning. C3−/−;SRPX2−/Y double-knockout mice exhibit phenotypes associated with C3−/− mice rather than SRPX2−/Y mice, which indicates that C3 is necessary for the effect of SRPX2 on synapse elimination. Together, these results show that SRPX2 protects synapses against complement-mediated elimination in both the thalamus and the cortex.

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