For more than a decade, scientists have been collecting evidence for the involvement of a gene called NRG1 in mental illnesses, most notably in schizophrenia. Today, a research team led by Amanda J. Law, Ph.D., a 2006 NARSAD Young Investigator Grantee and winner of the Foundation’s 2011 Baer Prize for Innovative and Promising Research, has published details of how a particular version of the protein encoded by the NRG1 gene is expressed in the very young brain. This work in turn suggests how a defect in NRG1 expression in brain cells at the very beginning of life may increase risk that an individual will develop schizophrenia.
When the NRG1 gene instructs a cell to manufacture a protein, the result will be dozens of NRG1 proteins, each one slightly distinct and capable of performing different biological “work” in the cell. The fact that multiple versions of a protein can be encoded by a single gene is a consequence of what scientists call alternative splicing—in which enzymes make “edits” to the gene’s instructions, which are spelled out in DNA “letters.” This is what enables our total set of 20,000 genes to make hundreds of thousands of different proteins.
Dr. Law, of the University of Colorado, Denver, School of Medicine and colleagues including Joel E. Kleinman, M.D., Ph.D., 2013 NARSAD Distinguished Investigator Grantee at the Lieber Institute for Brain Development, spent years closely studying a form of the NRG1 protein called NRG1-IV. Their earlier findings on NRG1-IV and its genetic regulation in schizophrenia were published in the Proceedings of the National Academy of Sciences in 2006 and the Journal of Biological Chemistry in August, 2007. Even more specifically, they scrutinized the properties of a novel variant of the NRG1 protein, called NRG1-IVNV.
In their paper appearing online today in The American Journal of Psychiatry, the team breaks new ground in figuring out exactly when NRG1 isoforms (or “versions”) are expressed during early prenatal and postnatal human brain development and when NRG1-IVNV is manufactured by brain cells. Significantly, NRG1-IVNV is made only from the sixteenth week of gestation—when the fetal brain is just beginning to take shape—until the third year of life. After that, this version of the protein is not detectable in brain samples, demonstrating what was previously suspected: the protein functions to support early brain development.
The most intriguing discovery made by Dr. Law’s team is about what happens to the NRG1-IVNV protein in people who have a specific gene mutation called rs6994992, which has previously been associated with schizophrenia. In people who have two copies of the schizophrenia-risk allele (one inherited from each parent, for example), something goes wrong with the NRG1 gene. During the critical window beginning in the second trimester of pregnancy and extending until age three, expression of the NRG1-IVNV protein is abnormally low in these individuals, the team discovered.
They are not yet sure how this occurs. But they suspect that having two copies of the rs6994992 schizophrenia risk allele increases risk for the illness, in part by interfering with the proper expression of the NRG1-IVNV variant, a protein that the brain appears to need in the very beginning of life. Dr. Law says this work leads to an increased understanding of the biological events that occur during early brain development and how they might work to increase risk for developing schizophrenia. Her team is now investigating the neurobiological role of the protein and how changes in its expression impact the development and function of brain cells.