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Further aging and neurodegeneration relevant FOXP2 targets

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FOXP2 and Vitamin D effect on ZNS


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 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 binding of TARBP2 domain to siRNA led to the formation of homogenous serum-stable complex with targeting potential. Further, uptake of the complex in Neuro-2a, IMR32 and HepG2 cells analysed by confocal microscopy and fluorescence activated cell sorting, revealed selective requirement of GM1 for entry. Remarkably, systemic delivery of the fluorescently labelled complex (TARBP-BTP:siRNA) in ΑβPP-PS1 mouse model of Alzheimer's disease (AD) led to distinctive localization in the cerebral hemisphere. Further, the delivery of siRNA mediated by TARBP-BTP led to significant knockdown of BACE1 in the brain, in both ΑβPP-PS1 mice and wild type C57BL/6. The study establishes the growing importance of fusion proteins in delivering therapeutic siRNA to brain tissues.” (Haroon et al., 2016, p. 1)

PIK3K


Gabbouj et al. (2019) describe in „Altered Insulin Signaling in Alzheimer's Disease Brain - Special Emphasis on PI3K-Akt Pathway“ the PI3K-Akt signalling pathway, involved in microglia and astrocytes, as an important player in T2D pathogenesis and insulin mediation. Decreased levels of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) subunits and decreased Akt kinase phosphorylation is associated with AD, amyloid-β and tau pathologies. TWD intake leads to altered PI3K subunits-levels and of intranasal insulin to enhancement of PI3K-Akt signalling, improved memory in human trials.

PIM1

PRAS40 phosphorylation is regulated by Pim1 Velazquez et al. (2016) gave a strong evidence for interconnection between the mammalian target of rapamycin (mTOR), proline-rich AKT substrate, PRAS40-phosphorylation-levels and Aβ, tau pathologies and cognitive deficits.


BACE1

Das, B. and Yan, R. (2017) described in „Role of BACE1 in Alzheimer's synaptic function“ that Aβ is generated from amyloid precursor protein (APP) via proteolytic cleavage by β-site APP cleaving enzyme 1 (BACE1) and BACE1 inhibition reduces Aβ-level in humans. BACE1 inhibitors could be an effective AD remedy.

NFE2L2

Otter et al. (2010) illustrated in „Nrf2-encoding NFE2L2 haplotypes influence disease progression but not risk in Alzheimer's disease and age-related cataract“ how one haplotype allele of NFE2L2 gene, encoding the main regulators of the defence system against oxidative stress, age-related cataract and AD, Nrf2-protein, was associated with 2 years earlier age at AD onset and 4 years earlier age at surgery for posterior subcapsular cataract.

According to Joshi and Johnson (2012)“The Nrf2-ARE pathway: a valuable therapeutic target for the treatment of neurodegenerative diseases“ neurodegenerative relevant NF-E2 related factor-overexpression has a positive impact on Amyotrophic lateral sclerosis, Alzheimer’s disease and Parkinson. A cis-acting antioxidant response element regulates phase II detoxification enzymes via ARE-Nrf2 binding with the help of Keap1, a culin 3-based E3 ligase that targets Nrf2 for degradation, sequesters Nrf2 in cytoplasm. Disruption of Keap1-Nrf2 interaction or genetic overexpression of Nrf2 has a positive effect on oxidative stress.

Pajares et al. (2016) identified in „Transcription factor NFE2L2/NRF2 is a regulator of macroautophagy genes“ the transcription factor NFE2L2/NRF2 (nuclear factor, erythroid 2 like 2) as a regulator of autophagy gene expression and its relevance to amyloid β precursor protein, MAPT/TAU and AD. According to ENCODE for BACH1 and MAFK, that bind the NFE2L2-regulated enhancer ARE, 27 putative AREs in 16 autophagy-related genes were identified and twelve of these sequences were validated as NFE2L2 regulated AREs in 9 autophagy genes after NFE2L2 activation with sulforaphane.


Saad El-Din et al. (2020) describe in „Active form of vitamin D analogue mitigates neurodegenerative changes in Alzheimer's disease in rats by targeting Keap1/Nrf2 and MAPK-38p/ERK signaling pathways“ the Nrf2 as a promising target for the prevention of Alzheimer's disease and vitamin D, its analogue, Maxacalcitol as crucial for improving AD cognitive functions via Keap1-Nrf2 signalling pathway.


Rojo et al. (2017) also confirmed in „NRF2 deficiency replicates transcriptomic changes in Alzheimer's patients and worsens APP and TAU pathology“ NRF2 as a crucial regulator of multiple stress responses, which also protects against inflammation and proteotoxicity and ageing is associated with decline of its level. Young adult AT-NRF2-KO mice showed deficits in long term potentiation in the perforant pathway, learning and memory.


Bahn et al. (2019) showed in „NRF2/ARE pathway negatively regulates BACE1 expression and ameliorates cognitive deficits in mouse Alzheimer's models“ BACE1 as the rate limiting Aβ generation enzyme. AD is accompanied by BACE1 and a BACE1 mRNA-stabilizing antisense RNA elevation. NRF2/NFE2L2 represses the BACE1 and BACE1-AS-expression via ARE promoters binding, independent of redox regulation. Also NRF2 improves cognitive deficits in animal models of AD, so the authors regard NRF2 as a possible key factor in prevention of early pathogenic process in AD.


KEAP1


Kerr et al. (2017) associate in „Direct Keap1-Nrf2 disruption as a potential therapeutic target for Alzheimer's disease“ Nrf2 with cell protection and an attractive therapeutic target for the prevention of neurodegenerative diseases, including Alzheimer’s disease (AD), provided in vivo evidence that specific inhibition of negative regulator of Nrf2 Keap1 can prevent neuronal toxicity in response to the AD-initiating Aβ42 peptide. Lithium, an inhibitor of the Nrf2 suppressor GSK-3, prevented Aβ42 toxicity in Nrf2 independent way.

JAK / STAT signalling


Nevado-Holgado et al. published 2019 „Genetic and Real-World Clinical Data, Combined with Empirical Validation, Nominate Jak-Stat Signaling as a Target for Alzheimer's Disease Therapeutic Developmen“, where they combined GWAS results with the current knowledge of molecular pathways, real-world clinical data from six million patients, RNA expression across tissues from AD patients and rodent models and showed that the degree of comorbidity of these diseases with AD correlates with the strength of their genetic association with molecular participants in the Janus kinases/signal transducer and activator of transcription pathway. They demonstrated Aβ induction by JAK-STAT anomalies and identified these genes as a potential target for therapeutic approach.


SERPINH1


Aβ and cytokines, involved in microglial activation, play a crucial role in neuroinflammation and AD. Yoo et al. published 2015 „ Amyloid-beta-activated human microglial cells through ER-resident proteins“ . They performed a proteomic analysis of Aβ-stimulated human microglial cells by stable isotope labelling with amino acids in cell culture combined with LC-MS/MS and clarified ER-resident proteins-level of PDIA6, PDIA3, PPIB and SERPINH1 was altered by 1.5 fold or greater. The researchers suggested that ER proteins play an essential role in human microglial activation by Aβ and could be important therapeutic targets for treatment of AD.


Ezrin-Radixin-Moesin complex.


α-secretases cleave the amyloid precursor protein to neuroprotective soluble APP ectodomain. Darmellah et al. (2012) show in „ Ezrin/radixin/moesin are required for the purinergic P2X7 receptor (P2X7R)-dependent processing of the amyloid precursor protein“ that the activation of ezrin, radixin, and moesin proteins is required for the P2X7R-dependent proteolytic processing of APP leading to sAPPα release and the ERM down-regulation via siRNA blocked it and P2X7R stimulation triggered its phosphorylation. Ezrin must translocate to the plasma membrane to interact with P2X7R and enzymes Rho kinase and the MAPK modules ERK1/2 and JNK act upstream of ERM, whereas a PI3K activity is triggered downstream.


Vega et al. (2018) also demonstrated in „Ezrin Expression is Increased During Disease Progression in a Tauopathy Mouse Model and Alzheimer's Disease“ that the increased Ezrin-level leads to the early stages of neurodegeneration in tauopathy models and human disease.


According to Oswald et al. (2017) „The FOXP2-Driven Network in Developmental Disorders and Neurodegeneration“ these proteins are involved in nervous system myelination, neuroinflammation, amyloid precursor protein formation, Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, Lewy body dementia and Parkinson's disease (Devanna et al.,2014) Different of these targets play an important role in aging and can be affected via caloric restriction. FOXP2-driven network enclosures DCDC2, CDH4, Ezrin-Radixin-Moesin complex, SERPINH1, JAK/STAT signaling,CDH4,DICER1, TARBP2, PIK3K, PIM1, NFE2L2,BACE1, KEAP1, Nrf2 and are important for nervous system development, maintenance, and functioning.

Other signalling pathways affect regulation of receptor-mediated endocytosis AβOs activated p38, mitogen-activated protein kinase, FOX P2 dependent MAPK (Review Wohlgemuth et al, 2014)

and ERK1/2 signalling pathways via the α7nAChR, which in turn results in AβO internalization.


MAPK signalling is implicated downstream of Aβ–PrPC–Fyn Alzheimer’s Amyloid-β oligomers (rescue cellular prion protein induced tau reduction via the Fyn pathway. Mitogen-activated protein kinase signalling pathways are involved in regulating alpha7 nicotinic acetylcholine receptor-mediated amyloid-beta uptake in SH-SY5Y cells, (Yan et al., 2014; Chen et al., 2013)

Also adipokines like adiponectin and leptin are AD-relevant. Adiponectin regulates glucose, lipid and energy metabolism and insulin sensitivity in many tissues via AdipoR1 and -R2 receptors and AMPK, p3-MAPK, PPAR-α and NF-kβ signalling is involved in these processes. (Chandran et al., 2003; Yamauchi et al., 2002; Soodini and Hamdy, 2004)


FoxP2-mi RNA modulation in neurological processes Several studies on songbirds explained how the expression and effects of FOXP2 are influenced by the miRNAs. According to Haesler et al. (2004) and Teramitsu et al. (2004) miRNA expression is indirectly proportional to the FOXP2 level. According to Mohd et al. (2017)intronic miR-3666 modulates different FOXP2 functions such as neuronal growth and development and may contribute to the pathogenesis of schizophrenia and autism. According to Haesler et al. „Incomplete and Inaccurate Vocal Imitation after Knockdown of FoxP2 in Songbird Basal Ganglia Nucleus Area X“ (2007) the reduction of FoxP2 in Area X impaires neuronal dendritic development and learning of singing patterns in young zebra finches. This impairment can be a result of negative miRNAs effect on FOXP2 (Shi et al., 2013). Hessler's group detected with the help of dual luciferase assays, western blotting, Area X tissue dissection, RNA isolation and in situ hybridization that miR-9 and miR-140-5p as well as FoxP2 Expression in Area X was non-linear during vocal learning, so the decline of FoxP2 expression was slow during the growth of the zebra finches, whereas its decline in adult males during undirected vocalisation took place within a few hours. This suggests that mRNA decay does not happen during

transcriptional repression. The researchers proposed a thesis that mRNA decay, induced by the vocalization and mediated by the miRNAs, provides a rapid response to environmental changes, which are necessary for social behaviour. Using lentivirus-mediated RNAi it was possible to prevent accurate song imitation by juveniles. (Haesler et al., 2007; Haeston and White, 2015)

In „Multiple microRNAs regulate human FOXP2 gene expression by targeting sequences in its 3 'untranslated region“ (2014) Fu et al. identified the untranslated UTR3 region of the FOXP2 gene as a regulatory element . Using the microRNAs that interact with this region, they were able to control FOXP2 expression. The FOXP2 mRNA has an approximately 4 kb 3 'untranslated region (3' UTR). It is twice as long as its protein-coding region. This indicates that FOXP2 can be regulated by miRNAs. The expression patterns of let-7a, miR-9 and miR-129-5p in human foetal cerebellum reflect their role in the regulation of FOXP2 expression during early development. These results suggest that various genetic and environmental factors may contribute to speech development. The associated neuronal developmental disorders are influenced, among others, by the miRNA-FOXP2 regulatory network.

Clovis et al. (2012) found that miR-9 and miR-132 could prevent ectopic Foxp2 expression on 3'UTR, which leads to disruption of radial migration in the neocortex of mouse embryos.

HFS diet showed neuroprotective affects, via miR-21 miR-22, miR-34 and miR-101, wich decreases expression of E2F3 and SIRT1 (Kumazaki et al., 2013) , but also via miR-146a, miR-200 and let-7.

Interestingly anti-aging natural products isoflavone, (-)-epigallocatechin-3-gallate, 3,3′-diindolylmethane, indole-3-carbinol, Curcumin positively affects Alzheimer, cardiovascular diseases, atopic asthma, Crohn’s disease, acute and chronic kidney injury, myeloma, glioblastoma, chronic lymphocytic leukaemia, cell lymphoma, osteosarcoma, colo-rectal-, breast-, non-small cell lung cancer and Helicobacter Pylori caused Ulcus. Berberine positively affects hyper-lipemia, cardiovascular diseases, diabetes, colorectal adenoma and Helicobacter pylori caused Ulcus too. It would be interesting to investigate if these effects are congruent with miR expression.

Influence of FOX genes on aging and aging-associated diseases

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