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The FEDORA That May Increase Risk of Depression in Women

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A small study examining both humans and mice has identified a gene regulator that may function as a controller of major depression specifically in females.

The research was published in Science Advances.

The study identified a long non-coding (lnc) RNA molecule, called RP11-298D21.1 (named by researchers as FEmale DepressiOn lncRNA (FEDORA)), that was expressed in lower levels in healthy women compared to healthy men, but which became upregulated in women with depression. The findings, say the authors, are relevant in the context of major depressive disorder (MDD), which affects twice as many women as men.

What are lncRNAs?

lncRNAs are one of the many types of RNA transcribed from DNA. They are usually longer than 200 nucleotides. They have several roles, but function primarily as a gene regulator by controlling the production and editing of other RNA molecules. They are highly expressed in the brain.

Postmortem analysis

The study, led by researchers at the Icahn School of Medicine at Mount Sinai, followed up on previous research suggesting that lncRNAs were regulated differently in people with MDD compared to healthy controls.

Here, the team looked instead at lncRNAs found at different levels in healthy men and women. What jumped out at the team was that these differences disappeared in people with MDD. The researchers received postmortem samples of men and women who had died with MDD. These were compared to control samples taken from age- and sex-matched controls. Looking in the prefrontal cortex of these patients, a region of the brain often linked to higher thinking and cognitive processes, the team noted that out of 762 lncRNAs with baseline expression differences between the sexes, 65.9% lost their differences in samples with MDD.

“These findings suggest that lncRNAs play a key role in regulating sex differences in the brain and that this pattern is corrupted by MDD,” write the authors.

The authors looked for lncRNAs whose expression was specifically increased in women with MDD, eventually highlighting FEDORA.

Modified mice

Their initial exploration of FEDORA involved experiments with mice genetically modified to express the human lncRNA in brain cells – neurons and oligodendrocytes – in their prefrontal cortices. These animals showed increased anxiety- and depression-associated behaviors, measured through a battery of behavioral tests. However, these changes were seen only in female mice. Further analysis of the microphysiological effects of human FEDORA expression in mice showed that the lncRNA altered how the mice’s neurons communicated through synaptic connections and altered the thickness of the insulating myelin sheath surrounding neurons – which is produced by oligodendrocytes.

Bringing the study full circle back to human data, the team looked at the levels of FEDORA in the bloodstream of MDD cases versus healthy controls, both in males and females. These participants were patients in a study of the rapidly acting antidepressant ketamine. This cohort enabled the researchers to look at the levels of FEDORA before and after treatment. As expected, women with MDD had higher levels of FEDORA in their bloodstream as compared to women without MDD. No such effect was noted in men.

After ketamine treatment, the team were unable to detect a significant change in the levels of FEDORA in women with MDD, although a regression analysis showed that the lncRNA was reduced most in the patients who received the most significant antidepressant benefit from ketamine.

In their discussion section, the authors acknowledge that teasing out the role of a single lncRNA in a disease as complex as MDD is a task that “presents many challenges” – for one, mice do not normally express FEDORA. Their findings that mice behavior is nonetheless altered in a similar way to humans suggests that “human-specific lncRNAs such as FEDORA arose later in evolution as an additional layer of regulation of increasingly complex molecular pathways already established in earlier mammals such as mice.” More analysis of the molecular mechanisms of sex differences in depression, they suggest, should quickly follow.

Reference: Issler O, van der Zee YY, Ramikrishnan A et al. The long noncoding RNA FEDORA is a cell type– and sex-specific regulator of depression. Sci. Adv. 2022. Doi: 10.1126/sciadv.abn9494