MicroRNAs and schizophrenia

NEW YORK—Schizophrenia, one of the more well-known mental disorders, is also one of the more complex, thought to be caused by genetics as well as chemical imbalances. Some of the latest research out of the Icahn School of Medicine at Mount Sinai, recently published in Cell Reports, focused on genetics to identify a potential risk factor for schizophrenia. Researchers from Icahn—led by Dr. Kristen Brennand, assistant professor of psychiatry at the Icahn School of Medicine at Mount Sinai, and Dr. Gang Fang, assistant professor in the Department of Genetics and Genomic Sciences, Icahn School of Medicine—turned skin cells into brain neurons and found that certain microRNAs (miRNAs) were under-expressed in the brains of studied schizophrenia patients.

The results appeared in a paper titled “Dysregulation of miRNA-9 in a Subset of Schizophrenia Patient-Derived Neural Progenitor Cells.”

One miRNA in particular, miR-9, is a risk factor that controls the activity of hundreds of genes. The team found that this miRNA was significantly under-expressed in cells from four schizophrenia patients, compared to six control individuals. These findings were repeated in a larger sample from the National Institutes of Health of 10 patients with childhood-onset schizophrenia and 10 controls. miR-9 is only the second significant miRNA linked to schizophrenia, but it is thought that there might be others involved as well.

The genes managed by miR-9 seem to play a role in the fetal development of neurons and where they eventually settle in the brain. According to the paper, if these genes are less active than they should be, there's a higher likelihood that the brain will be miswired. Research from both Brennand's team and other scientists in the field show that many of the genes found to be linked to this disease tend to be those that are expressed during fetal development, despite the fact that symptoms generally appear in adulthood.

As the authors note in the paper, “We show that microRNA-9 (miR-9) is abundantly expressed in control neural progenitor cells (NPCs) but also significantly downregulated in a subset of [schizophrenia] NPCs. We observed a strong correlation between miR-9 expression and miR-9 regulatory activity in NPCs as well as between miR-9 levels/activity, neural migration, and diagnosis. Overexpression of miR-9 was sufficient to ameliorate a previously reported neural migration deficit in [schizophrenia] NPCs, whereas knockdown partially phenocopied aberrant migration in control NPCs. Unexpectedly, proteomic and RNA sequencing (RNA-seq)-based analysis revealed that these effects were mediated primarily by small changes in expression of indirect miR-9 targets rather than large changes in direct miR-9 targets; these indirect targets are enriched for migration-associated genes. Together, these data indicate that aberrant levels and activity of miR-9 may be one of the many factors that contribute to SZ risk, at least in a subset of patients.”

These results also validate those of another study, one published March 9 in JAMA Psychiatry. That study reported that a genetic screen, taken from blood samples of 35,000 schizophrenia patients, found either low expression or mutations in the hundreds of genes controlled by miR-9.

Fang noted that one of the challenges of this work was the fact that “miR-9 was not the only miRNA that is differentially expressed in cells from schizophrenia patients compared to control participants.”

“In fact, tens of miRNAs reached statistical significance, and we wanted to identify a smaller number of key players. We took a systems biology approach, where we integrated miRNA expression, gene expression, global gene regulatory networks and proteomic data,” Fang explained, adding that their approach “found evidence suggesting miR-9 has the most significant change of regulatory activity in addition to the expression change of itself. We hope this general approach will also help the discovery of additional genetic regulators of schizophrenia and other diseases.”

“Schizophrenia is a very complex disorder that is believed to be strongly genetically influenced — there are probably more than 1,000 genes contributing to its development, some or many of which will affect individual patients,” said Brennand. “The better we are able to fill in the pieces to this very difficult puzzle, the more we can think about treatment, and, better yet, prevention.”