Oleic acid triggers hippocampal neurogenesis by binding to TLX/NR2E1

Kandel, Prasanna; Semerci, Fatih; Bajić, Aleksandar; Baluya, Dodge L.; Ma, Long; Chen, Kevin; Cao, Austin C.; Phongmekhin, Tipwarin; Matinyan, Nick; Choi, William T.; Jiménez-Panizo, Alba; Chamakuri, Srinivas; Raji, Idris; Chang, Lyra; Fuentes‐Prior, Pablo; MacKenzie, Kevin R.; Benn, Caroline; Estébanez‐Perpiñá, Eva; Moore, David D.; Young, Damian W.; Maletić-Savatić, Mirjana

doi:10.1101/2020.10.28.359810

Cited by 5 publications

(6 citation statements)

References 37 publications

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“…Several natural and synthetic molecules have been identified as potential TLX ligands, demonstrating both agonist and inverse agonist effects in vitro [152,153]. Recently, the monounsaturated omega-9 fatty acid oleic acid was identified as a TLX endogenous ligand, synthesized by NSCs/NPCs to trigger their cell cycle and promote neurogenic progeny [154]. This is consistent with the general ability of nuclear receptors, such as steroids and phospholipids, to bind lipophilic molecules such as steroids and phospholipids [155,156].…”

Section: The Nuclear Receptor Tlxsupporting

confidence: 52%

Glial PAMPering and DAMPening of Adult Hippocampal Neurogenesis

Parkitny

Maletić-Savatić

2021

Brain Sciences

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Adult neurogenesis represents a mature brain’s capacity to integrate newly generated neurons into functional circuits. Impairment of neurogenesis contributes to the pathophysiology of various mood and cognitive disorders such as depression and Alzheimer’s Disease. The hippocampal neurogenic niche hosts neural progenitors, glia, and vasculature, which all respond to intrinsic and environmental cues, helping determine their current state and ultimate fate. In this article we focus on the major immune communication pathways and mechanisms through which glial cells sense, interact with, and modulate the neurogenic niche. We pay particular attention to those related to the sensing of and response to innate immune danger signals. Receptors for danger signals were first discovered as a critical component of the innate immune system response to pathogens but are now also recognized to play a crucial role in modulating non-pathogenic sterile inflammation. In the neurogenic niche, viable, stressed, apoptotic, and dying cells can activate danger responses in neuroimmune cells, resulting in neuroprotection or neurotoxicity. Through these mechanisms glial cells can influence hippocampal stem cell fate, survival, neuronal maturation, and integration. Depending on the context, such responses may be appropriate and on-target, as in the case of learning-associated synaptic pruning, or excessive and off-target, as in neurodegenerative disorders.

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Section: The Nuclear Receptor Tlxsupporting

confidence: 52%

Glial PAMPering and DAMPening of Adult Hippocampal Neurogenesis

Parkitny

Maletić-Savatić

2021

Brain Sciences

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“…Histone deacetylase 3 (HDAC3), HDAC5, LSD1 (a histone demethylase), Atrophin1, and BCL11A have been reported to interact with TLX to regulate the expression of target genes, and has been validated in human Y79 retinoblastoma cells (Wang and Xiong, 2016). Study has shown that oleic acid triggers hippocampal neurogenesis by binding to TLX/NR2E1 and changes it to a transcriptional activator from a transcriptional repressor of cell cycle and neurogenesis genes (Kandel et al, 2020). Thus, through TLX (orphan nuclear hormone receptor), oleic acid could indirectly activate Wnt7a expression, suppresses the expression of p21 via a p53-dependent mechanism, promotes EGFR signaling in brain cells, and modulates the mitogen-activated protein kinase (MAPK) pathways (Wang and Xiong, 2016) and enhances STAT1 function (Beiting et al, 2015).…”

Section: Resultsmentioning

confidence: 99%

Bioinformatics exploration of olive oil: molecular targets and properties of major bioactive constituents

Fatoki

Akintayo

Ibraheem

2021

OCL

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Olive oil possesses medicinal properties which include antimicrobial, antioxidant and anti-inflammatory, anti-diabetes, and anti-cardiovascular diseases. Oleic acid is the most abundant (95%) constituent of olive oil and others include linoleic acid, oleuropein, oleanolic acid, maslinic acid, melatonin, and others. The objective of this study is to predict the molecular targets and properties of key bioactive components of olive oil in human. Bioinformatics methods, which involved pharmacokinetics prediction, target prediction and gene network analyses, were used. The results showed that oleic acid has similar targets with linoleic acid, and showed significant probability of binding to several targets such as fatty acid-binding proteins in the adipose, epidermal, liver and muscle as well as alpha, delta and gamma peroxisome proliferator-activated receptors (PPARs). Carbonic anhydrase showed to be the only significant target of tyrosol, while protein-tyrosine phosphatase 1B, and CD81 antigen were targeted by maslinic acid and oleanolic acid. This study has applauded oleic acid, linoleic acid and tyrosol as olive oil bioactive constituents that have several potential pharmacological effects in humans that modulate several enzymes, receptors and transcription factors. The future work will be to investigate the effects of oleic acid on fatty acid-binding proteins and telomerase reverse transcriptase; melatonin on quinone reductase 2; tyrosol on carbonic anhydrase II; maslinic acid and oleanolic acid on protein-tyrosine phosphatase 1B.

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“…Despite limited knowledge on TLX and the lack of TLX modulator tools for functional studies, there is preliminary evidence for a great potential of TLX in neurodegenerative diseases. In the brain, TLX regulates the maintenance of NSC populations and neurogenesis. , It governs behavior and activation of NSCs through directly controlling the expression of the tumor suppressor pten and the cyclin-dependent kinase inhibitor p21, thereby enabling re-entry in the cell cycle. ,, Accordingly, the putative TLX activator oleic acid ( 46 ) was recently shown to induce NSC mitosis and neurogenesis in mice . Thus, maintaining NSCs in the brain in a proliferating, self-renewing state and preventing their differentiation appear to be key roles of TLX. ,,− NSCs are found in at least two main regions of the adult (human) brain, the subgranular zone of the dentate gyrus and the subventricular zone of the lateral ventricle, from where NSCs initiate the formation of new neurons. ,, TLX appears to be a key regulator of this process by maintaining a balance between proliferating NSCs and differentiated neurons. ,, The absence of TLX, accordingly, caused an entire loss of neurogenesis .…”

Section: Nuclear Receptors and Neurodegenerationmentioning

confidence: 99%

“…NMR experiments were employed to orthogonally validate a direct interaction between TLX and the retinoids, which revealed chemical shift perturbations and line broadening . Another recent study has discovered oleic acid ( 46 ) as a putative endogenous TLX ligand that is capable of switching TLX activity from transcriptional repression to cell cycle activation and was shown to be present in human NSCs.…”

Section: Nuclear Receptors and Neurodegenerationmentioning

confidence: 99%

Targeting Nuclear Receptors in Neurodegeneration and Neuroinflammation

2021

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Nuclear receptors, also known as ligand-activated transcription factors, regulate gene expression upon ligand signals and present as attractive therapeutic targets especially in chronic diseases. Despite the therapeutic relevance of some nuclear receptors in various pathologies, their potential in neurodegeneration and neuroinflammation is insufficiently established. This perspective gathers preclinical and clinical data for a potential role of individual nuclear receptors as future targets in Alzheimer's disease, Parkinson's disease, and multiple sclerosis, and concomitantly evaluates the level of medicinal chemistry targeting these proteins. Considerable evidence suggests the high promise of ligand-activated transcription factors to counteract neurodegenerative diseases with a particularly high potential of several orphan nuclear receptors. However, potent tools are lacking for orphan receptors, and limited central nervous system exposure or insufficient selectivity also compromises the suitability of well-studied nuclear receptor ligands for functional studies. Medicinal chemistry efforts are needed to develop dedicated high-quality tool compounds for the therapeutic validation of nuclear receptors in neurodegenerative pathologies.

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Oleic acid triggers hippocampal neurogenesis by binding to TLX/NR2E1

Cited by 5 publications

References 37 publications

Glial PAMPering and DAMPening of Adult Hippocampal Neurogenesis

Glial PAMPering and DAMPening of Adult Hippocampal Neurogenesis

Bioinformatics exploration of olive oil: molecular targets and properties of major bioactive constituents

Targeting Nuclear Receptors in Neurodegeneration and Neuroinflammation

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