New Studies Search for Clues to Mental Illness in Gatekeepers of Gene Expression
Molecules called microRNAs may hold some answers
• Science Update
What goes awry in the brain to cause mental illness may ultimately be traced to glitches in genes - but not necessarily the parts of genes commonly suspected. Rather than the areas of genes that code for proteins, the secrets may be hidden in mysterious short sequences of genetic material called microRNAs. MicroRNAs help regulate gene expression — the turning on-and-off of genes to produce those proteins. Unraveling how this molecular machinery works is the focus of newly funded grants from the National Institute of Mental Health.
Studies totaling $3 million per year over the next five years will seek to pinpoint how these "noncoding" parts of the genome increase vulnerability to schizophrenia, bipolar disorder, autism and other mental illnesses.
"The more complex the organism, the bigger the role played by these noncoding segments, which account for as much as 98 percent of the human genome" said Dr. Thomas Lehner, chief of NIMH's Genomics Research Branch. "We've just begun to scratch the surface of understanding these vast, uncharted regions of our biological inheritance."
The new studies focus on a type of genetic material called ribonucleic acid (RNA), best known for transcribing DNA into proteins essential for vital functions of the body, from development to digestion to thinking and memory. It's now known that RNAs can have other functions as well. Small RNAs, including microRNAs, regulate gene expression via a process known as RNA interference. Abnormalities in microRNAs have been implicated in cancers and Fragile X syndrome.
Recently, researchers funded partly by NIMH uncovered the first evidence that expression of microRNAs may be altered in schizophrenia. A team led by grantee Diana Perkins, MD, MPH, University of North Carolina, found differences when she and her colleagues compared the brains of 15 deceased schizophrenia and schizoaffective-disorder patients with the brains of 21 deceased people who had not had psychiatric disorders. The differences were found in the prefrontal cortex, which regulates such functions as thinking and decision-making and has been implicated in schizophrenia.
Among 264 microRNAs screened in brains of those who had schizophrenia, levels of 15 were lower — and one higher — than normal. This suggested that there may be glitches in the formation of microRNAs in schizophrenia that could affect protein production. Perkins and colleagues reported their results in the February 2007 issue of Genome Biology.*
One of the recipients of the new NIMH grants, Rockefeller University's Thomas Tuschl, PhD, discovered that RNA interference could be used to experimentally switch genes on and off in mammalian cells. This opened up a new approach to genetics discovery and potential therapeutic applications. So far, about 500 microRNAs have been identified, but thousands likely exist, and little is known about what they do in the brain.
With his new NIMH funding, Tuschl hopes to develop an "expression atlas" of microRNAs involved in mental illnesses. He will bring to bear newly developed technologies, animal models, and the resources of three laboratories to pinpoint the role of a subset of microRNAs highly expressed in the brain.
"Understanding the specific interactions of microRNAs and the network of genes they target and regulate may ultimately contribute to our understanding and treatment of debilitating mental illnesses," said Tuschl.
Similarly, grantee Linda Brzustowicz, MD, of Rutgers University, will search for evidence that some microRNAs may be improperly expressed in schizophrenia and bipolar disorder. Her team will try to identify variant forms of microRNAs linked to the disorders, winnow a list of a dozen such suspect forms, and characterize how they might work to produce illness.
In another study, grantee Michael James, PhD, at the Queensland Institute of Medical Research, will tap Australia's Twin Registry to examine versions of 605 suspect genes for psychiatric disorders that could alter target sites for microRNAs.
Among other projects funded under the new initiative, Xinyu Zhao, Ph.D., University of New Mexico, is investigating a possible role of small RNAs in depression. Her work suggests that small RNAs may play a critical role in the "epigenic" process by which early maternal behavior can influence gene expression in an offspring, with enduring effects on its stress circuitry and behavior.
Flipping the Gene Switch: microRNA's
MicroRNAs help switch genes on-and-off via RNA interference. In this process, the sequence of letters in a microRNA attaches to its mirror counterpart in a larger messenger RNA. If the letters match perfectly, the messenger RNA is destroyed and no protein is made, while a less-than-perfect match merely inhibits the gene's expression. In the latter case, if the cell later needs the protein, the microRNA detaches and gene expression resumes. Each of thousands of messenger RNAs are regulated by multiple specific microRNAs.
*Perkins DO, Jeffries CD, Jarskog LF, Thomson JM, Woods K, Newman MA, Parker JS, Jin J, Hammond SM. microRNA expression in the prefrontal cortex of individuals with schizophrenia and schizoaffective disorder. Genome Biol. 2007;8(2):R27. PMID: 17326821