Summary: Long non-coding RNAs (lncRNAs) show strong, region- and sex-specific changes in depression. The primate-specific lncRNA LINC00473 is reduced in the prefrontal cortex of depressed women but not men. Experimental evidence links LINC00473 to female resilience to stress and helps explain part of the higher prevalence of depression in females.
Source: Mount Sinai Hospital
Researchers at Mount Sinai report that long non-coding RNAs (lncRNAs) expressed in the brain can influence mood and contribute to sex-specific vulnerability and resilience to depression. In a study published in Neuron, the team identified LINC00473 as a key lncRNA that is downregulated in the prefrontal cortex (PFC) of depressed women, providing a possible molecular explanation for why women experience depression at roughly twice the rate of men.
“Our study highlights a new family of molecular regulators that could help researchers better understand the biological mechanisms underlying depression, particularly in women,” says Orna Issler, PhD, lead author and postdoctoral researcher at the Nash Family Department of Neuroscience and The Friedman Brain Institute, Icahn School of Medicine at Mount Sinai. “These insights may guide the development of more effective treatments for a disorder that remains the leading cause of disability worldwide.”
Genetic studies indicate that roughly one-third of depression risk is heritable, while environmental factors—especially stress—account for much of the remainder. LncRNAs represent an additional layer of regulation: they are epigenetic regulators that alter gene expression without changing DNA sequence. Although research into lncRNAs and mood disorders is still emerging, the Mount Sinai team found that lncRNAs are robustly dysregulated in depression in ways that depend on brain region and biological sex.
“The complex primate brain appears to rely on lncRNAs to regulate higher-order functions such as mood,” explains Dr. Issler. “Disruption of these lncRNA-driven processes can contribute to mood disorders like depression and anxiety, and those disruptions can be sex-specific.” In particular, the team identified LINC00473 as a neuronal, primate-specific lncRNA that is reduced in the PFC of depressed females but not males. Functional experiments showed that restoring LINC00473 in adult PFC neurons promotes stress resilience specifically in female mice.
To prioritize lncRNAs potentially involved in depression, the investigators screened thousands of candidate transcripts in human brain tissue and applied bioinformatic filters to identify the most promising targets. LINC00473 emerged as a lead candidate. Using viral-mediated gene delivery, the researchers re-expressed LINC00473 in adult mouse PFC neurons and observed a female-specific increase in resilience to stress. This behavioral effect in females was accompanied by changes in synaptic function and gene-expression profiles, consistent with a sex-dependent molecular mechanism. Complementary experiments in human neuron-like cells supported a role for LINC00473 in regulating gene networks relevant to mood and synaptic physiology.
Evidence from the study suggests that LINC00473 may act as a CREB effector, influencing downstream gene expression and neuronal physiology in a manner that promotes resilience in females. The sex-specific regulation and function of LINC00473 offer a plausible molecular contributor to the marked sex differences seen in depression prevalence and response to stress.
“These results open a window onto a new class of molecular targets that could explain mechanisms of depression susceptibility and resilience, especially in women,” says Eric J. Nestler, MD, PhD, corresponding author and Nash Family Professor of Neuroscience at Icahn School of Medicine. “Long non-coding RNAs may point the way to improved diagnostic markers and more effective, targeted treatments for depression. While additional studies are needed, this work provides a promising roadmap for future research.”
Collaborators on the project included researchers from the University of Pittsburgh, University of Texas Southwestern Medical Center, and Massachusetts General Hospital. The study was supported by grants from the National Institute of Mental Health (NIMH), Hope for Depression Research Foundation (HDRF), and the Brain & Behavior Research Foundation (NARSAD).
Highlights
- LncRNAs are broadly and robustly altered in depression in brain region- and sex-specific patterns.
- LINC00473 is selectively downregulated in the cortex of depressed females, not males.
- Restoring LINC00473 expression in mouse PFC promotes stress resilience only in females.
- LINC00473 influences gene expression and neuronal physiology in a sex-specific manner.
Study summary
Depression disproportionately affects women. This study finds that long non-coding RNAs represent roughly one-third of differentially expressed genes in the depressed human brain and display intricate sex- and region-specific regulation. The primate-specific, neuron-enriched LINC00473 is reduced in the PFC of depressed females. Reintroducing LINC00473 into adult mouse PFC neurons reproduces a female-specific protective effect against stress, accompanied by synaptic and gene-expression changes in females. These findings nominate LINC00473 as a female-specific driver of stress resilience that is dysregulated in female depression.
Funding: National Institute of Mental Health (NIMH), Hope for Depression Research Foundation (HDRF), Brain & Behavior Research Foundation (NARSAD).
Original research: Open access — “Sex-Specific Role for the Long Non-coding RNA LINC00473 in Depression,” by Issler et al., published in Neuron.
Feel free to share this genetics and neuroscience news.