Researchers discover protein’s impact on schizophrenia

<p>A team of Rutgers researchers from Bonnie Firestein’s lab assisted last semester in the discovery of a protein to detect the symptoms of schizophrenia in order to treat the polygenic disorder.</p>

A team of Rutgers researchers from Bonnie Firestein’s lab assisted last semester in the discovery of a protein to detect the symptoms of schizophrenia in order to treat the polygenic disorder.

A recent breakthrough may soon allow researchers to treat schizophrenia before symptoms even appear.

Bonnie Firestein, a professor in the Department of Cell Biology and Neuroscience, helped discover an effect of nitric oxide synthase 1 adaptor protein that might lead to schizophrenia through research funded by the Brain and Behavior Research Foundation.

“Too much of this protein is what happens in people with schizophrenia, or at least a subset of them,” she said. “[This is] due to what we call an associated allele, which means that there is a change in the DNA [so that more mRNA is made].

This change in the DNA was found by Linda Brzustowicz, a professor in the Department of Genetics, Firestein said. Other research teams confirmed the results through various ethnic groups.

NOS1AP affects how a brain develops, said Kristina Hernandez, a student in the Graduate School of New Brunswick, in an email. It helps determine the shape of neurons.

The gene encodes a protein that affects how something called a N-methyl-D-aspartate receptor works, Firestein said. The NMDA receptor binds a neurotransmitter known as glutamate, which plays a role in how a person learns and remembers.

Excess amounts of this protein specifically cause issues with how the cortex is made, she said. During brain development, cells migrate out and become neurons. This process repeats, with each successive wave of cells migrating further out.

“What happens in the case when you have too much NOS1AP is that the cells get stuck, they don’t go out as far,” she said. “You have incorrect wiring and you also have incorrect layering.”

NOS1AP also affects the shape of neurons, said Damien Carrel,an assistant professor at Paris Descartes University, in an email. It can limit how much a neuron’s “branches” develop, which would have an effect on their ability to communicate.

Having excessiveNOS1AP in the brain did not mean a person would definitely get schizophrenia, which is a polygenic disorder, Firestein said. A symptomatic person needs to have multiple altered genes, and may also be affected by environmental factors.

Rather, having higher levels of NOS1AP only increases how susceptible a person might be to the disorder, she said. Furthermore, not all patients with this disorder have the associated allele.

“The cause could be genetic,” said Carrel, a Rutgers alumnus. “It was found that some people have small modifications in the gene coding NOS1AP that seem to increase their risk [of developing] the disease.”

It is thought that the modifications could cause over-expression of NOS1AP, he said. This theory has yet to be proven.

The region of the brain thought to be involved with schizophrenia is called the dorsolateral prefrontal cortex, Firestein said. Control levels of the protein were studied in samples of the region.

“Our studies used post-mortem brain tissue, and since there is degradation of the tissue, we don’t know how much NOS1AP there is in that region of the brain,” she said.

Her team also used a model to study the effects shortly after birth, she said. They now believe that NOS1AP may have an impact during embryonic development.

NOS1AP was discovered through its interactions with neuronal nitric oxide synthase, Carrel said. This protein is responsible for information transmission in the nervous system.

Three isoforms, or different shapes of the same protein, were studied by Firestein’s team, she said. Two isoforms were focused on.

Reversing the effects of NOS1AP on neurons is the next step in the research, Hernandez said. The goal is to treat patients while the brain is still developing to reduce the symptoms caused by schizophrenia.

“We know […] that the expression of NOS1AP is largely reduced in the brains of patients treated with antipsychotics,” Carrel said. “It would be interesting to develop a method to decrease NOS1AP levels and see if this can reduce the symptoms associated with schizophrenia.”

Editor's note: A previous version of this story labeled Damien Carrel as a post-doctoral fellow at the Université Pierre et Marie Curie.

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