Tubulin could be a potential biomarker for depression

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Scientists have zeroed in on a structural protein as a new target for the diagnosis and treatment of depression, according to research recently published in Journal of Neuroscience.

The protein tubulin provides structure to cells and assists in many cellular processes, but it also plays a role in depression.

A modified form of tubulin anchors the protein Gαs to lipid rafts, fatty structures floating in the cell membrane. In depressed people, Gαs gets stuck in lipid rafts and cannot trigger the production of cAMP, a molecule necessary for quick messaging in the brain.

Imaging studies have shown that people with depression have less cAMP in their brains, which is remedied after successful treatment.

Singh et al. examined the amount of modified tubulin in the brains from people who were not depressed as well as those from people with depression who died by suicide and by other causes.

All the brains contained the same amount of modified tubulin, but the brains of people with depression had less modified tubulin in the lipid rafts.

This could allow more tubulin to trap Gαs in the lipid rafts, preventing cAMP production.

Tubulin could provide a diagnostic marker of depression and a target of antidepressant treatment.


Obesity predominantly develops in response to increased consumption of energy-dense diets and a sedentary lifestyle1. Rare genetic mutations in the central melanocortin pathway are responsible for the development of monogenic obesity in humans2.

The main clinical consequences of obesity are abnormalities characteristic of the metabolic syndrome (e.g., hypertension, insulin resistance, or dyslipidemia) and an increased risk of diseases such as cancer 3,4.

Furthermore, obesity has been linked to depression 5,6, with both epidemiological and clinical studies demonstrating a positive association between these two disorders7. Nonetheless, the precise mechanism underlying the interaction between obesity and depression has yet to be elucidated.

Although the neuropathophysiology of depression remains unclear, abnormalities in monoamine signaling components, such as serotonin and dopamine, have been implicated in the development of this condition 8.

Clinical observations around mid-90s suggested that depression results from decreased monoamine function in the brain 8. Some of the key drugs currently used to treat depression target monoamine signaling 8; however, not all patients benefit from such intervention9.

The presence of obesity, or overweight, places patients with major depression at risk of resistance to the antidepressant fluoxetine, regardless of the severity of depression at baseline 10.

When compared with patients of normal body weight, overweight and obese patients showed a substantially slower response to antidepressant treatment, less improvement in neuroendocrinology and cognitive processing, and less antidepressant-induced weight gain 11. This observation suggests the involvement of unique pathways for depression in the overweight and obese population.

The neurocircuitry of depression is complex and involves portions of the limbic system, such as hippocampus, amygdala, thalamus, cortex, and hypothalamus 12. From all these brain regions that play a crucial role in depression, hypothalamus is the main regulator of energy homeostasis, located in a region highly vascularized with ample communication with the periphery, and has been implicated in both obesity and depression 13.

Signaling via 3′, 5′-cyclic AMP (cAMP) appears to have a key role in the pathophysiology and pharmacology of depression 14. Even though the mechanism of action of antidepressants is very complex and not well understood, it is believed that antidepressant treatments involve adaptations of the cAMP signaling cascade15.

Generation of cAMP by adenylyl cyclase activity occurs after stimulation of the G protein-coupled receptors (GPCRs). Antidepressants often increase coupling of stimulatory G proteins with adenylyl cyclases 16, thereby increasing both the activity of cAMP-dependent protein kinase A (PKA) 17 and the expression and function of cAMP response element-binding protein (CREB) 18. Protein phosphorylation by PKA regulates a vast variety of neuronal functions 19.

In depression signaling via cAMP may be impaired by cyclic nucleotide phosphodiesterases (PDEs), which provide the sole route for cAMP degradation in cells 20. Of all the different PDEs, members of the PDE4 gene family play a major role in regulating cognition and depressive disorders 21.

The PDE4 gene family (PDE4A, PDE4B, PDE4C, and PDE4D) gives rise to >20 different isoforms22. PDE4C is the only one not expressed in brain according to previous studies 23.

Although much of the PDE4 sequence is conserved between isoforms, the unique N-terminal region confers direct isoform-specific targeting to intracellular signaling complexes 24 and interaction with anchor/scaffold proteins 25, allowing the fine tuning of cAMP signaling to discrete subcellular locations and specific pathways26.

The most important neuronal pathway for human obesity is the central melanocortin signaling pathway, as the majority of genes responsible for human monogenic obesity are components of this pathway2.

The central melanocortin pathway is regulated by dietary fatty acids 27,28, which bind to different fatty acid receptors, a subfamily of the GPCRs superfamily, to convey intracellular signaling pathways 29.

There are four main free fatty acid (FFA) receptor divisions according to the length and saturation of fatty acids they bind to: FFA receptor 1 (FFAR1 also known as GPR40) that binds medium and long chain saturated fatty acids such as palmitic acid 30, FFA receptor 3 (FFAR3 also known as GPR41) and FFA receptor 2 (FFR2 also known as GPR42) that both bind short chain fatty acids 31, and finally the FFA receptor 4 (FFAR4 also known as GPR120) that binds ω-fatty acids 32.

Just as PDEs may have a mechanistic role in the development of depression, they may also influence the development of obesity. Members of the PDE4 family can interact with GPCRs 33 via β-arrestin proteins, which act as scaffolds to localize PDE4s to ligand-activated GPCRs 34,35.

Even though a positive association between obesity and depression has been established, which of the two plays a causative role for the development of the other one and what is the molecular mechanism(s) of this phenomenon remains unknown. I

n the present study, we found that either dietary or genetically induced obesity (GIO) in mice lead to depression phenotype and this phenomenon occurs via the disruption of the cAMP/PKA signaling pathway.

Furthermore, we identified that loss of PDE4A can prevent both dietary and genetically induced depression-like behavior phenotype in mice. In addition, we found that the consumption of a fat-dense diet leads to an influx of dietary fatty acids specifically in the hypothalamus.

These fatty acids can directly modulate the PKA signaling pathway that is responsible for the development of depression.

These findings suggest that the influx of saturated fatty acids due to the consumption of an high-fat diet (HFD) can alter the cAMP/PKA signaling cascade and that result in the development of depression phenotype.

Discussion

Using behavioral paradigms in mice, we demonstrated, as have others previously 40,41, that either DIO or GIO can be causative for the development of depression. This relationship is mechanistically coupled to regulation of cAMP/PKA signaling in the hypothalamus. Interestingly, such an effect is independent of the increases in body weight caused by consumption of an HFD or induction of stress as shown by the EPM behavioral assay.

Protein and mRNA analysis identified PKA signaling as the main pathway altered in the hypothalamus after consumption of an HFD. PKA is a tetrameric enzyme that phosphorylates its protein targets when cAMP binds its regulatory subunits 42.

The PKA signaling cascade and depression have been previously linked 14 – but not in the context of diet composition – as chronic administration of antidepressant drugs or electroconvulsive seizures targets PKA signaling in the brain 16,43.

The present study reveals that the accumulation of different fatty acids in the hypothalamus alters PKA signaling, suggesting a potential mechanism of action of dietary fatty acids in the regulation of mood disorders, such as depression, via the PKA signaling pathway.

Although mice show depressive behavior after 3 weeks on HFD, most of the PKA-mediated gene expression manifest at 8 weeks. This can be explained by the fact that transient changes in cAMP can lead to both short and delayed/extended gene expression changes. For example, short- and long-term memory actions 44.

Another potential mechanism that may result in the development of obesity-induced depression phenotype is inflammation45. Indeed, in this regard, palmitic acid has been shown to activate Toll-like receptor 4 (TLR4) signaling 46.

To the best of our knowledge, the present findings are the first to show that the consumption of an HFD induces an influx of dietary fatty acids specifically in the hypothalamus, leading to an impairment of the cAMP/PKA signaling cascade and this downregulation of the PKA pathway can be implicated behaviorally for the development of depression in mice.

Signaling via cAMP is downregulated among patients with depression47. Many antidepressant drugs act by upregulating molecules involved in cAMP signaling, which is the major regulator of PKA 15. Cyclic nucleotide PDEs provide the sole route for cellular degradation of cAMP 48, with each PDE isoform displaying distinct roles and intracellular localization 26.

PDE4 enzymes are major regulators of the cAMP signaling in the brain and localize in brain regions that are associated with reinforcement, movement, and affect, all of which actions are altered among people with depression 49.

A similar mechanism of the action of antidepressant drugs that act by the upregulation of the cAMP signaling pathway has been proposed for rolipram, a selective PDE4 inhibitor with known antidepressant activity in mice 50.

Chronic administration of rolipram leads to a sustained elevation of cAMP levels51 and increases the expression of CREB, brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB), all of which are believed to facilitate the action of antidepressants 18,52.

Despite initial promise, the therapeutic potential of rolipram as an antidepressant has been limited by compromising adverse side effects, particularly nausea and vomiting 50,53 because this compound inhibits all PDE4 isoforms 54.

Identifying the specific PDE4 isoform that mediates the antidepressant action of rolipram could enable the development of selective inhibitors that offer therapeutic effects with minimal adverse reactions 55.

Here we show that the loss of PDE4A in vivo prevented the depression-like phenotype observed in mice in response to DIO or GIO. PDE4A5 appears to be the specific PDE4 isoform responsible for the depression phenotype. Consumption of an HFD increases the PDE4 activity specifically in the hypothalamus.

Of note, such an increase was abolished in the PDE4A−/− mouse model. Levels of PDE4A5 mRNA and protein (including the phosphorylated form) were higher in hypothalamic samples collected from mice fed an HFD versus an ND. Interestingly, it has been previously shown that PDE4A5 interacts with disrupted in schizophrenia 1 (DISC1), a major genetic risk factor for the development of schizophrenia 56.

Therefore, our novel findings suggest that PDE4A5 may have potential therapeutic importance for the design of a PDE4A5, isoform-selective inhibitor that would minimize the adverse effects associated with the use of a generic PDE4 inhibitor (note that the cognate enzyme in humans is termed PDE4A4).

Such a novel, isoform-selective inhibitor might rescue the depression phenotype caused by obesity.

Considerable focus has been placed on developing agents targeting monoamines and their metabolism8 for the treatment of depression. However, 50% of all patients do not respond to the currently available antidepressant drugs 57.

Moreover, the majority of overweight and obese individuals do not respond to current antidepressant treatments, which suggested that other molecular pathways are involved in the development of depression among this subpopulation 10.

Interestingly, a previous connection between activation of PDE4A isoforms by fatty acids has been established in immune cells 58,59.

FFA receptors in the brain might explain how dietary fatty acids can link food intake with mood disorders such as depression. Regulation of the expression of different FFA receptors at the mRNA level, especially FFAR1, in the hypothalamus in response to DIO and GIO represent a potential mechanism to regulate depression.

Despite the potential role of FFAR1 signaling in the hypothalamus for lipid sensing that controls energy balance and food intake 13, the present study shows for the first time that FFAR1 signaling might also play an important role in mood disorders such as depression.

There was a trend for the FFAR3 to increase with the consumption of an HFD, however, it did not reach statistical significance. This might be due to the small number of animals used for the real-time PCR analysis.

Further studies, however, are needed to characterize any potential involvement of the short chain fatty acid receptor FFAR3 in contributing to the phenomenon we uncover here, namely of a novel, obesity-induced depression phenotype.

As such, in addition to the established role of fatty acid receptors predominantly acting in the regulation of metabolic pathways, such as insulin secretion 60, data in this study suggest that fatty acid receptors in the brain may promote signaling related to mood disorders.

In conclusion, our study shows that FFAR1 associates with the PDE4A5 isoform. This discovery highlights the possibility that developing small molecules aimed at inhibiting the association between PDE4A5 and FFAR1 could provide novel therapeutics for treating patient’s depression caused by their diet.

Further studies are required, however, to investigate the potential for either a direct interaction of FFAR1 and PDE4A5 or an indirect one involving β-arrestin. Determination of the exact interaction sites for these species is needed to better understand that pathway and to develop novel therapeutics based upon disrupting the interaction of such components.

Indeed, small molecules that selectively target the interaction of the PDEs with FFA receptors might represent a new generation of antidepressants with increased specificity for either overweight and/or obese individuals.


Source:
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