Blocked Brain Protein Linked to Depression in Mice, Humans

Portrait of a sad womanDepression is a global problem. The latest numbers from the WHO rank it first amongst disabling diseases worldwide over other contenders like heart disease, stroke and cancer. That’s because many who live with depression struggle with it for the entirety of their lives. A recent survey done in U.S. workers found that nearly a quarter suffered from depression at some point, and 40% of them take an average of 10 days off work per year because of it.

In spite of the widespread burden of the disease, much remains unknown about what is happening in the brain when someone becomes depressed. While selective serotonin reuptake inhibitors (SSRIs) like Paxil, Zoloft and Celexa are some of the most successful depression drugs, the neurotransmitter serotonin, a chemical messenger widely used in the brain that they boost, is thought by many experts to be only one part of the story.

Researchers have continued to search for the underlying molecular process that leads to depression in the hope that a better understanding could also bring more targeted and effective treatments to a population desperately in need of help. A new study out this week has brought us one step closer to that goal.

The researchers were interested in a protein called β-catenin. The protein had been studied in the past and had been shown to play a role in a variety of psychiatric diseases, but the nuances of that role weren’t known. In the nerve cells of the brain, β-catenin has two main roles: It helps to decide which genes are activated to make proteins and also helps to form the structure around areas where nerve cells communicate with each other.

That first gene-activating role is done in partnership with another oddly named molecular switch called Wnt. Past studies had shown that this Wnt switch was important in a key part of the brain found to be involved in depression called the nucleus accumbens. Mice who had a poorly working Wnt switch were more stressed in social situations. Those with better working switches did better under stress. Because the researchers knew β-catenin was closely related to Wnt, they wondered if the levels of that protein might also be important in the stress response.

They tested this hypothesis first in mice. They genetically modified them to make large amounts of β-catenin and put them in stressful situations with their normal counterparts to see how they would respond. Time and again, those with high levels of the protein seemed more resilient and less stressed under these trying situations.

Intrigued, the team then tried blocking β-catenin’s ability to activate genes to see if this might have the opposite effect. Sure enough, these blocked mice did worse than their normal counterparts in stressful situations.

The question now was to figure out why this was happening. To do this, they looked at human brains from individuals who had died with depression. Here, too, they saw low levels of β-catenin in the same region of the brain linked to Wnt: the nucleus accumbens.

Using mice, the research team traced the action of this protein through the pathways in the brain and found that a type of nerve cell called a D2 neuron relied heavily on β-catenin. If the activity of β-catenin was blocked in D2 neurons in the nucleus accumbens, the mice had trouble with stress. If their levels were high, they were protected against it.

Finally, the team looked to see which genes β-catenin was targeting. They found that one gene called Dicer1 that plays a role in controlling other genes was particularly affected by losing β-catenin action. Along with other genes, Dicer1 may be helping the brain to adapt to stressful situations by turning on needed genes in the brain.

The research blows open a whole new area for uncovering how depression might occur in the brain. Not only does it show a molecular basis of why someone may become depressed, but in finding a single protein responsible it opens up an entirely new target for drugs to help those with depression. By making drugs that help to increase the activity of β-catenin in the nucleus accumbens, it may be possible to make people less susceptible to depression and the harmful effects of stress on the brain.