Discovery of a Key Protein’s Role in Stress Resilience Paves Way to Possible New Treatments
Discovery of a Key Protein’s Role in Stress Resilience Paves Way to Possible New Treatments
A research team at the Icahn School of Medicine at Mount Sinai, which included a number of NARSAD Grantees, has identified a protein called β-catenin that helps regulate the brain’s resilience to stress and anxiety. By tracing the “biological network” associated with β-catenin, the scientists say they have provided a foundation for discovering targets for a potential new generation of treatments that would promote stress resilience and combat certain forms of depression. These results, reported in a study published November 12th in Nature, “offer a template for future studies to induce resilience in inherently more susceptible individuals,” the researchers say in the journal article.
The study’s lead scientist was Eric J. Nestler, M.D., Ph.D., a 1996 NARSAD Distinguished Investigator Grantee and member of the Foundation’s Scientific Council.
Dr. Nestler’s team began this study knowing that β-catenin plays an important role in depression and other brain illnesses. But since the protein has several known biological functions, it has been difficult untangling the specific way in which it is implicated in the nexus of stress, anxiety, and depression. In the newly reported work, the team manipulated β-catenin expression in a part of the brain called the nucleus accumbens (NAc). Prior work by Dr. Nestler and colleagues had proven the importance of a particular signaling pathway in the NAc involved in generating resilience to social stress.
In the new work, the team looked at the NAc when β-catenin was both overexpressed and underexpressed. Unusually high levels of the protein prevented the mice from developing social avoidance, an indicator of depression-like behavior. In contrast, totally blocking β-catenin expression in the NAc promoted susceptibility to stress in mice that were subjected to mild “social defeat” stress––in essence, a form of comparatively gentle bullying. Much of the rest of the research involved tracing the biological mechanisms behind these links between β-catenin and resilience.
The team found that β-catenin is a key regulator of behavioral resilience, in part through its action in spurring the activity of small RNA molecules called microRNAs. These molecules, in turn, are the product of a gene called Dicer1, which proves to be a target of β-catenin. Such details are critical to understanding the power of the research, for it is this detailed biology––the network formed by the gene, its microRNA products, and β-catenin––that could ultimately lead to treatments to promote stress resilience.
“These data provide a new pathway to find novel and potentially more effective antidepressants,” said Dr. Nestler. “Our findings are distinct from those implicating serotonin and other neurotransmitter systems previously linked with depression or resilience against it.”
Other NARSAD grantees involved in this research included: Jian Feng, Ph.D. (2013 NARSAD Young Investigator Grantee) and Rosemary Bagot, Ph.D. (2014 NARSAD Young Investigator Grantee), both of the Icahn School of Medicine at Mount Sinai; Vincent F. Vialou, Ph.D. (2010 NARSAD Young Investigator Grantee) of INSERM; Deveroux Ferguson, Ph.D. (2012 NARSAD Young Investigator Grantee) of the University of Arizona; Carol A. Tamminga, M.D. (two-time NARSAD Distinguished Investigator Grantee and Scientific Council Member) and Subroto Ghose, M.D., Ph.D. (2007 NARSAD Young Investigator Grantee) of the University of Texas Southwestern Medical Center at Dallas; and Rachael L. Neve, Ph.D. (1997 NARSAD Independent Investigator Grantee) of the McGovern Institute for Brain Research at MIT.
