Novel mechanisms in depression: focus on telomere biology and epigenetic regulation

Depression is a complex disorder with an average lifetime prevalence from 11.1% to 14.6%. It causes serious disability and is a significant public health problem worldwide. The etiology of depression is heterogeneous and multifactorial. Traditionally, researchers have tried to investigate depression from biochemical, genetic, environmental and behavioral perspectives. Since few biomarkers are available, diagnosis and treatment are still based on clinical assessment and are far from satisfactory. In recent years, depression has been proposed to be a state of “accelerated biological aging”, with an increased risk of comorbidity with other ageing-related conditions such as diabetes, cardiovascular disease and dementia. There is accumulating evidence to support that depression itself is in fact a state that involves telomere dysfunction, a prominent feature in the ageing process. Epigenetic regulation, with an emerging role in a number of complex disorders, constitutes a fusion between the results of genetic, biochemical and environmental factors. The aim of this thesis was to investigate the pathophysiology of depression with a focus on mechanisms that are perturbed in telomere biology and epigenetic regulation. Specifically, in paper I and III: telomere length and the genetic variation in the hTERT gene were examined in relation to lithium treatment, to depression disorder and depressive episodes in bipolar disorder in human cohorts. In paper II, we used a genetic rat model of depression (FSL) to study hippocampal telomere length and telomerase activity, and investigated the mechanism of how lithium affects telomere length. The epigenetic mechanisms potentially involved in depression, specifically DNA methylation/hydroxymethylation and miRNAs were investigated in the prefrontal cortex region of the FSL rats in paper IV and V, respectively. The major finding from the thesis work includes 1) telomere lengths were decreased in saliva DNA from patients with adult depression 2) genetic variation in hTERT may influence the susceptibility to depression 3) telomeres and telomerase activity are dysfunctional in the hippocampus of the depressed FSL rats 4) long-term lithium treatment is associated with longer telomeres in bipolar disorder especially when therapeutically efficacious 5) lithium treatment may normalize hippocampal telomerase dysfunction through activation of β-catenin in the rat 6) sodium butyrate exerts antidepressant-like effect and the suggestive epigenetic effects may include DNA methylation changes that are mediated by the demethylation-facilitating enzyme TET1 in the rat 7) elevation of cytokine Il6 in the prefrontal cortex is associated with depression-like states and may involve disturbance in let-7 biogenesis in the rat 8) physical exercise appears to normalize Il6 and let-7 levels through regulatory processes upstream of primary miRNA transcription in the rat.

List of scientific papers

I. Martinsson L, Wei Y, Xu D, Melas PA, Mathé AA, Schalling M, Lavebratt C, Backlund L. Long-term lithium treatment in bipolar disorder is associated with longer leukocyte telomeres. Transl Psychiatry. 2013 May 21;3:e261.
https://doi.org/10.1038/tp.2013.37

II. Wei Y, Backlund L, Wegener G, Mathé AA, Lavebratt C. Telomerase dysregulation in the hippocampus of a rat model of depression. Normalization by lithium. Int J Neuropsychopharmacol. 2015: pyv002.
https://doi.org/10.1093/ijnp/pyv002

III. Wei Y, Martinsson L, Liu JJ, Forsell Y, Schalling M, Backlund L, Lavebratt C. hTERT genetic variation in depression. [Submitted]

IV. Wei Y, Melas PA, Wegener G, Mathé AA, Lavebratt C. Antidepressant-like effect of sodium butyrate is associated with an increase in TET1 and in 5-hydroxymethylation levels in the Bdnf gene. Int J Neuropsychopharmacol. 2014 Oct 31;18(2). pii: pyu032.
https://doi.org/10.1093/ijnp/pyu032

V. Wei Y, Liu JJ, Åberg E, Brené S, Wegener G, Mathé AA, Lavebratt C. Elevation of Il6 is associated with disturbed let-7 biogenesis in a genetic model of depression. [Manuscript]