Influence of FOX genes on aging and aging-associated diseases. Elena Tschumak

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 learning, memory and motor function. (Holson et al., 1997) Rats with a vitamin A deficiency also showed poor motor performance when they learned new movements. (Carta et al., 2006) In addition vitamin deficit had a negative impact on striatal development. Striatal progenitor cells could not differentiate without RA signals (Krezel et al., 1998), (Chatzi et al.,2011). Acute RA-level reduction in mice led to impaired induction in synaptic grading and impairment of hippocampal LTP and LTD, which was, however, reversible. Normal synaptic plasticity was quickly restored in this phenotype with the help of vitamin A supplementation. (Misner et al., 2001)

      According to Boccardi et al. „Beta-carotene, telomerase activity and Alzheimer's disease in old age subjects“, 2019 β-carotene significantly and positively correlated with telomerase activity, independent of gender, Β-carotene plasma level was associated with AD diagnosis and

      β-carotene may modulate telomerase activity in old age. Moreover, lower plasma β-carotene levels, correlating with peripheral telomerase activity, are associated with AD diagnosis independent of multiple covariates. This way FOXP2 genes can have a further effect on aging and tumorigenesis.

      According to Devanna et al. (2014) „FOXP2 drives neuronal differentiation by interacting with retinoic acid signalling pathways“ FOXP2 reduces the expression of DDL3 and RARβ (retinoic acid receptor). The CARET study showed that high-dose beta-carotene (a precursor of retinoic acid (vitamin A) for an extended period was suspect to cause by 18 percent smokers lung cancer and it is known that FoxP2 is high expressed in lungs (Li, et al., 2004; Zhou et al., 2008;Groszer et al., 2008). FoxP2-coexpression with the transcription factor homeodomain Nkx2.1 in the lung was described by Li et (2012) FoxP2 interaction with the CtBP1 co-repressor may be involved in tumor suppression of breast cancer. CtBp interacts with the oncofactor BRCA1 / 2 (Chinnadurai G., 2009) (Deng et al. 2012) It would be of great interest to investigate whether the pathogenic vitamin A effect in this case is due to the interactions with FOXP2 which play a role in many oncological processes.

       CDH4

      According to Liu et al., 2012 total cerebral brain volume depends on CDH4-level, involved also in AD.These findings suggest that Dicer1 may be a target in AD therapy.

       DICER1

      Yan et al. (2019) explained that Dicer1 is reduced in APPswe/PSEN1dE9 mice and is regulated by Nrf2 and Brain Dicer1 is down-regulated in a mouse model of Alzheimer’s disease via Aβ42-induced repression of nuclear factor erythroid 2-related factor 2. The researchers studied unexploited roles of Dicer1 in AD and a novel way of Dicer1 regulation. Their results make hope that Dicer1 may be a target in AD therapy.

       TARBP2

      

      According to Haroon et al., 2016 „A designed recombinant fusion protein for targeted delivery of siRNA to the mouse brain“TARBP2 Binding Protein fused to a brain targeting peptide that binds to monosialoganglioside GM1. “Conformation-specific