Influence of FOX genes on aging and aging-associated diseases. Elena Tschumak
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Название: Influence of FOX genes on aging and aging-associated diseases
Автор: Elena Tschumak
Издательство: Bookwire
Жанр: Медицина
isbn: 9783754131572
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FOXP2 target RUNX2 binds to the 1alpha, 25-dihydroxyvitamin D3 receptor. (Paredes et al., 2004). The 25-dihydroxyvitamin D3 receptor is encoded by VDR involved in immune response and tumor suppression. Together with the VDR express multiple immune relevant genes, eg. they regulate SPAG5. (Stephens and Morrison., 2014). The SPAG5 encodes a protein required for the correct function of mitotic spindles, which also regulates cell stress-induced apoptosis. (Thedieck et al., 2013) Together with FOXP2, RUNX2 regulates aging relevant vitamin D (Patrick and Ames, 2014), (Hawes et al., 2015) and other interaction partners, such as: CREB (Oury et al., 2010)
Aging relevant H3K27ac and H3K14ac are acetylated via p300/CBP and its co-activator CREB . cAMP responsive CREB expression is responsible to fasting. So CBP, CREB, CRTC2 and TAF-4 activate together gluconeogenesis genes (Altarejos and Montminy, 2011 )
The RUNX2 also affects GTF2I (Lazebnik et al., 2009), there is some evidence for feedback processes because both GTF2I and RUNX2 expression are regulated by the AUTS2. (Oksenberg et al., 2014) The AUTS2 cooperates with the PRC1, the GTF2I, the SATB2, the ZMAT3, the RELN and the TBR1.
Vitamin D-Esr1-Igf1 interaction effects molecular pathways relevant to Alzheimer’s disease and Molecular Neurodegeneration. (Landel et al.,2016)
Kaneko and colleges demonstrated that calcitriol regulates the expression of two human brain-related genes containing VDREs, tryptophan hydroxylase (Tph) and leptin. Landel et al, 2016 studied the effect of maternal vitamin D deficiency on fetal brain development and identified that these genes are also modulated in the brains of either Wt or Tg mice and found that the pups from deficient mothers display a modulated expression of Bdnf, Foxp2, Tgfb1 and Th, which are also affected in certain conditions of this study. Together with FOXP2, RUNX2 regulates aging relevant vitamin D (Patrick and Ames, 2014), (Hawes et al., 2015) and other interaction partners, such as: CREB (Oury et al., 2010).
Vitamins and aging
In general vitamins are also age-related factors. So, Vitamin D is important for ROS protection in the ZNS and for cell cycle regulation.( Pusceddu, 2015) Vitamin B2 is an antioxidant due to its involvement in the glutathione redox cycle (in glutathione reductase (Ashoori, 2014) and it is a cofactor in amino acid and lipid metabolism as well as in redox reactions. Riboflavin reduction increases lipid peroxidation. (Wang, 2011) Vitamin B6 reduces homocysteine concentrations and protects against cardiovascular diseases (Okura , 2014) Vitamin B12 is a cofactor for the methionine synthase (important for folate cycle and homocysteine re-methylation) and for the Methylmalonyl CoA mutase ( Hughes, 2013) Aging is associated with B12 reduction. Antioxidant Vitamin C (ascorbic acid) and dehydroascorbic acid are necessary for myelin, peptide amination, for synthesis of neurotransmitters and carnitine and it helps to recycle vitamin E and tetrahydrobiopterin, its deficiency is associated with amyloid-β plaques. ( Dixit, 2015) Like vitamin E (Gutierrez-Fernandez, 2015; Rinaldi, 2003) Vitamin A and retinoic acid are necessary for neurodevelopment (Touyarot , 2013) and its reduction is associated with aging, inflammation. It influences p21 and Alzheimer disease.
FOXP2 influence on RA receptor expression and its effect on the retinoic acid-mediated neuronal differentiation
Benítez-Burraco and Boeckx (2014) described in „FOXP2 drives neuronal differentiation by interacting with retinoic acid signaling pathways“ the importance of RA signalling and of FOXP2 for brain processes, the upregulation of RARβ by FOXP2 . The FOXP2 indirectly regulates the SIRT1 and other genes via RUNX-UTS2-TBR1-DYRK1A cascade and directly some SIRT1 target genes. The DYRK1A in turn phosphorylates the SIRT1. So there exists possible a connection between the FOXP2 and the RUNX2 via SIRT1. In addition, the SIRT1 directly controls thewith nuclear retinoid receptor proteins termed as retinoic acid receptors (RARs) and retinoid X RUNX2.The Dyrk1A also promotes de-acetylation of TP53, which is associated with carcinogenesis (Ni et al., 2005). TP53 induces PANDA lncRNA, which influence aging via binding the transcription factor NF-YA.
Sodhi and Singh, 2014 found in „Retinoids as potential targets for Alzheimer's disease“ that vitamin A and its derivatives, the retinoids, modulate several physiological and pathological processes through their interactions with nuclear retinoid receptor proteins termed as retinoic acid receptors (RARs) and retinoid X receptors (RXRs). Both have an antioxidant potential. Retinoid signalling exists in including amygdala, hypothalamus, hippocampus, striatum and cortex and its defects seem to be relevant for defects in learning, memory and for Alzheimer's disease. Retinoids also decrease pro-inflammatory cytokines- and chemokines-level by astrocytes and the microglia. RA exposure leads to an up-regulation of choline acetyltransferase (ChAT) level and activity, ameliorated the symptoms of AD and reduced amyloid accumulation and tau hyperphosphorylation in APP/PS1 transgenic mice and its isomers enhance, the expression of genes linked with cholesterol efflux e.g. apoe, abca-1 and abcg-1 proteins in astrocytes.
Also according to Das et al..2019 „Potential therapeutic roles of retinoids for prevention of neuroinflammation and neurodegeneration in Alzheimer's disease“ retinoids have an important impact on neural patterning, differentiation, axon outgrowth and brain function, impaired RA- signalling leads to oxidative stress, mitochondrial malfunction, neuroinflammation, neurodegeneration and Alzheimer's disease (associated with aggregated amyloid-beta and hyperphosphorylated tau protein). They also described loss of spatial learning and memory as a result of low RA-level, because retinoids inhibit expression of chemokines and neuroinflammatory cytokines in microglia and astrocytes, which are activated in Alzheimer's disease. Retinoic acid receptors stimulation decreases amyloids accumulation,neurodegeneration level, and thereby prevents pathogenesis of Alzheimer's disease in mice.
Shudo et al. published 2009 „Towards retinoid therapy for Alzheimer's disease. “This paper deals mainly with AD in relation to retinoic acid receptors (RARs: RARα, β and γ) and their ligands (retinoids), such as the endogenous RAR ligand all-trans-retinoic acid (RA), considering current knowledge about PD, ALS and other neurodegenerative diseases. “It is important to note that factors leading to the onset of these diseases are still poorly understood, and so there is a great deal of scope for novel therapeutic approaches. Recent findings indicate that the window of opportunity for enhancing or normalizing the growth of neuronal cells and promoting recovery from neurodegenerative diseases may be larger than previously thought.” (Shudo et al., 2009, p.1)
Another direct FOXP2 target is the general transcription factor GTF3C3, which plays an important role among others in apoptosis (Zhan Y, 2002).
According to Devanna et al. (2014) "FOXP2 drives neuronal differentiation by interacting with retinoic acid signalling pathways", FOXP2 interaction with retinoic acid makes cells more sensitive to RA effects and strengthens this way neuronal differentiation. This leads to increased neurite growth and branching as well as to decreased neuronal migration. These effects are particularly important in the striatum because speech-disabled people with a mutant FOXP2 gene have a pathology in this brain area. This gives further hint to the FOXP2 role in neuronal differentiation. The authors also mentioned that FOXP2 reduces DDL3 and RARβ (retinoic acid receptor) expression in the striatum.
In “Retinoic Acid Signaling: A New Piece in the Spoken Language Puzzle” (Rhijn et al. 2015) looked the researchers for evidence that the FOXP2 and RA pathways overlap. They analysed molecular, cellular and behavioural levels and found that FOXP2 changes RA receptor expression. These receptors directly control cellular response to RA. The retinoic acid receptor β (RAR β) was of particular interest because mice with the corresponding mutation showed severe movement deficits and its motor learning was severely impaired. (Krezel et al.) Increased RA level in pregnant rats led to behavioural problems and to impaired СКАЧАТЬ