January 2021

PSYCHIATRY

PROTEIN REGULATION NETWORK MAY INFLUENCE PSYCHIATRIC DISORDERS

Featuring: ​Peter Penzes, PhD
​
​​Homer1, a protein that’s important for neural plasticity and learning, is part of a large network of proteins in the brain that help ensure new connections are wired correctly, according to a Northwestern Medicine study published in Molecular Psychiatry.

These findings are good news for scientists searching for treatments for psychiatric disorders, according to Peter Penzes, PhD, the Ruth and Evelyn Dunbar Professor of Psychiatry and Behavioral Sciences, professor of Physiology and Pharmacology, and senior author of the study.

“This network means it may be easier to find treatments: because it’s all interconnected, we can look for more therapeutic pathways,” said Penzes, who is also director of the Center for Autism and Neurodevelopment.

Previous studies have shown Homer1 is important for brain development: genetically modified mice missing this protein show behavioral abnormalities, and genetic studies of humans have shown a lack of Homer1 is associated with psychiatric disorders such as autism, schizophrenia and depression. The protein is activated by electrical stimulation, including when new connections are made in the brain.

“When you learn something new, this induces expression of Homer1 in specific brain cells,” Penzes said.

However, until now, Homer1’s function was largely unknown, partly because scientists knew little about its protein-protein interactions.

“In the past, these interactions were identified one by one, but now the technology has changed and allows the identification of large networks of interactions,” Penzes said. “It puts these things in a very different context.”

The investigators used a computational neurology approach to search for protein partners of Homer1, finding a large network of interactions with another protein, ankyrin-G, at the center. Overexpression of ankyrin-G is known to be a major genetic risk factor for bipolar disorder, schizophrenia and autism, suggesting a direct link between Homer1 and these psychiatric disorders.

In collaboration with Jeffrey Savas, PhD, assistant professor in the Ken and Ruth Davee Department of Neurology Division of Behavioral Neurology and a co-author of the study, the team analyzed synaptic proteins in genetically modified mice that were lacking Homer1. They were surprised to find in these mice that much of the associated protein interaction network was upregulated, instead of downregulated.

“This shows that an important role for Homer1 in the brain is to keep levels of disease risk proteins such as ankyrin-G in check,” Penzes said.

The discovery of this network may be a boon to scientists searching for drug therapies for psychiatric disorders. Instead of having just a single pathway to test druggable targets upon, investigators can take advantage of the interconnectivity to possibly produce large-scale changes with a single drug.

“This shows that things are changing globally, and by altering one thing you might be able to alter the entire network,” Penzes said.

This work was supported by The National Institutes of Health grant R01MH107182 and an Individual Biomedical Research Award from The Hartwell Foundation.

This article was originally published in the Feinberg School of Medicine News Center on January 26, 2021. 
Peter Penzes, PhD, the Ruth and Evelyn Dunbar Professor of Psychiatry and Behavioral Sciences, professor of Physiology and Pharmacology, and director of the Center for Autism and Neurodevelopment, was the senior author of the study

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