The link between long noncoding RNAs and depression

Abstract

The major depressive disorder (MDD) is a relatively common mental disorder from which that hundreds of million people have suffered, leading to displeasing life quality, which is characterized by health damage and even suicidal thoughts. The complicated development and functioning of MDD is still under exploration. Long noncoding RNA (lncRNAs) are highly expressed in the brain, could affect neural stem cell maintenance, neurogenesis and gliogenesis, brain patterning, synaptic and stress responses, and neural plasticity. The dysregulation of certain lncRNAs induces in neurodevelopmental, neurodegenerative and neuroimmunological disorders, primary brain tumors, and psychiatric diseases. Although advances have been made, no fully satisfactory treatments for major depression are available, further investigation is requested. And recently data showed that the expression level of the majority of lncRNAs demonstrated a clear tendency of upregulation, and the certain dysregulated miRNAs and lncRNAs in the MDD have been proved to have a co-synergism mechanism, that is why we speculate lncRNA might get the capability to regulate MDD. Few identified lncRNAs have been deeply studied in detailed experiments up until now, little predictions of their function have been raised, and further researches is calling for discover their signal pathway and related regulatory networks.

Introduction

Depression is a comparatively common mental disorder, characterized by enduring sadness, anhedonia, feelings of guilt or low self-worth, disturbed sleep or appetite, feelings of tiredness, and poor concentration and even suicidal thoughts (Ansorge et al., 2007, Rao et al., 2015). Up to 2012, more than 350 million people suffer from depression all over the world, patients suffering from major depressive disorder (MDD) will get a 12-month prevalence of 6.6% and a lifetime prevalence of 16.2%, and women are twice susceptible compared to men (Thomson et al., 2014). Compared to unipolar depression patients, bipolar patients are much more likely to present to clinicians, while unipolar depression is more prevalent than bipolar disorder (Hirschfeld, 2014). The clinical presentation of patients with unipolar depression is more likely to show typical depressive symptoms including sad mood, anxiety, insomnia, and somatic depressive symptoms. However the clinical presentation of patients with bipolar disorder, are more likely to show “inverse” neuro-vegetative symptoms, particularly hypersomnia, increased appetite and weight gain (Hirschfeld, 2014). Current antidepressants, such as serotonin (5-HT) re-uptake inhibitors (SSRIs) were commonly applied in treating depression (Hetrick et al., 2007, Chaplin and Krishnadas, 2014). Recent years, advances have been made in improving the diagnosis and treatment of MDD patients, for example, many promising biomarkers have been intensively investigated for the early diagnosis of MDD and as treatment targets for novel drug development (Redei and Mehta, 2015). Despite these, many efforts still needed in future studies.

Though only less than 1% of the mammalian genome that are transcribed into mRNA, the major part of the genome is non-coding RNAs (ncRNA) what was previously considered as “transcriptional noise”, that do not encode information about proteins (Ma et al., 2015, Mckiernan and Greene, 2015). Long non-coding RNAs (lncRNAs) are those over 200 nucleotides in length and do not have a functional open reading frame (ORF) (Ma et al., 2013, Esteller, 2011). LncRNAs have multiple functions including the ability to regulate transcription/gene expression by recruitment of transcription factors, modulate mRNA processing, adjust post-transcriptional pathways (like translation, miRNA sponges and mRNA stability), DNA methylation and scaffold to organize and hold higher-order complexes, modulate chromatin structure by recruitment of histone and chromatin modifiers to specific genomic loci and so on (Salmena et al., 2011, Wang and Chang, 2011, Geisler and Coller, 2013). Thus, lncRNAs may play some roles in disease pathologic process, and intense investigations have been implemented to find new molecules and mechanisms of complex diseases, providing light on the potential of utilizing lncRNAs as the diagnosis, prognosis, and also promising treatment targets (Khorkova et al., 2015). Accumulating evidence showed that lncRNAs with a large number and diversity play an important regulator role in brain functions (Guennewig and Cooper, 2014). LncRNAs are highly expressed in the central nervous system, affecting neural stem cell maintenance, neurogenesis and gliogenesis, brain patterning, synaptic and stress responses, neural plasticity and cognitive function (Fenoglio et al., 2013, Fatica and Bozzoni, 2014, Spadaro and Bredy, 2012). For example, lncRNA brain cytoplasmic (BC1) is one of the first lncRNA characterized in the brain, is now known to regulate metabotropic receptor signaling (Centonze et al., 2007). Neurogenesis-associated lncRNAs were found to associate directly with REST, the transcription factor SOX2 and PRC2 component SUZ12, suggesting that lncRNAs may act as guides for these proteins. Importantly, knockdown of these lncRNAs by RNAi resulted in impaired neuronal differentiation, suggesting that lncRNAs are critical regulators of neurogenesis (Ng et al., 2012). Therefore, it provides a new perspective to determinate whether the development of MDD has certain underlying association with lncRNA, and if the hypothesis were plausible, what kind of detailed mechanisms involved in the process.

In this review, we discuss the role of some specific lncRNAs which may be important for understanding the pathophysiology of neuropsychiatric diseases, also have the potential as therapeutic targets. Especially we were highly interested in the potential role of lncRNA in regulating the relative signaling pathways, molecular mechanism and development of major depression disorder.