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

Alzheimer's disease relevant glycoprotein NCAM1. (Atz et al., 2007) ( Konopka et al., 2009) The FOXP2 also influences DISC1, (Walker et al., 2012), (Miyoshi et al., 2004), a Reelin receptor VLDLR (Adam et al., 2016), NURR1, PHOX2B, TBX22, SEBOX and FOXL1, CDH4 and CDH11, DICER1, RISC TARBP2, DICER1, EIF2C1-4 , DCDC2, KIF13B, PTPRQ, MSN, FOXP2 , NAKR1, SEBOX, MARVELD1, PHOX2B, MYH8, MYH13, PIK3K, PTPRQ, PIM1, NFE2L2, ERP44, KEAP1, JAK / STAT signalling, the phosphatase PTEN, BACE2, SERPINH1, CDH4 and the Ezrin-Radixin-Moesin complex. 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. The amount of satellite cells decreases with age (Brack et al., 2005; Collins et al., 2007; Gibson and Schultz, 1983) and like hematopoietic stem cells they change their Wnt and Notch pathways with the age as well as TGF-β and sFGF ligands and differentiate less to myogenic lineage and more to fibrogenic lineage Brack et al., 2007 Carlson et al., 2009 Carlson and Faulkner, 1989 Chakkalakal et al., 2012 ; Conboy et al., 2003, 2005; Sinha et al., 2014) and cytokine signalling via the JAK-STAT pathway (Price et al., 2014) and increase p38-MAPK signalling (Bernet et al., 2014; Cosgrove et al., 2014) Sousa-Victor et al., 2014 ). Wnt3, GH, TGF-β and IGF improve neurogenesis (Blackmore et al., 2009 Katsimpardi et al., 2014 ; Lichtenwalner et al., 2001; Okamoto et al., 2011; Pineda et al., 2013 ; Villeda et al., 2014 ).Growth differentiation factor 11 (GDF11)can improve NSC- and satellite cell function, but ist production decreases with aging. (Katsimpardi et al., 2014; Loffredo et al., 2013.; Sinha et al., 2014). At the same time high TGF-β levels disturb satellite cells and neuronal stem cells function (Carlson et al., 2009;) but growth differentiation factor 11 improves it. (Katsimpardi et al., 2014 ; Loffredo et al., 2013; Sinha et al., 2014).

      Kanekiyo and Bu showed 2014 that Low-density lipoprotein receptor-related protein 1 regulates cellular Aβ uptake and degradation in neurons, astrocytes, and microglia in brain parenchyma, and in vascular smooth muscle cells and pericytes in cerebrovascular. It also mediates Aβ clearance at the BBB by facilitating Aβ transport from brain to blood and Apolipoprotein E is a major ligand for LRP1 and influences AD risk by affecting Aβ aggregation, cellular uptake and degradation, apoE and Aβ “can interact with each other, they also share common receptors including LRP1, LDLR, and HSPG on cell surface. ApoE likely competes with Aβ for their receptor binding but can also facilitate cellular Aβ uptake by forming apoE/Aβ complexes depending on their concentrations, apoE isoform involved, lipidation status, Aβ aggregation status and receptor distribution patterns. Dissecting how LRP1 participates in apoE-mediated Aβ clearance will be critical to develop apoE-targeted therapy for AD.” (Kanekiyo and Bu, 2014, p. 7)

      FOXP2 controls expression of for Alzheimer's disease relevant PTEN (Oswald et al.,2017; Frere and Slutsky, 2016; Knafo et al., 2016; Zhang et al. 2006; Rickle et al., 2006) Mislocalization of Pten in murine brain was observed to correlate with down-regulation of Foxp2 and upregulation of Msn (Tilot et al., 2016)

      

      Further FOXP2 controls expression of for Alzheimer's disease relevant glycoprotein NURR1 Nurr1 was specifically expressed in glutamatergic neurons of the hippocampus of healthy brains and that these Nurr1‐expressing, Aβ‐positive glutamatergic neurons degenerated in an age‐dependent manner in 5XFAD mice and plays important roles in AD pathogenesis. (Moon et al.Nurr1, 2019)

      According to Oswald et al. (2017) „The FOXP2-Driven Network in Developmental Disorders and Neurodegeneration“ the transcription factor encoded by the new FOXP2 target NURR1 (also NR4A2, NOT) seems to be of special importance for normal dopaminergic functioning. So stimulation of NURR1 improves behavioural deficits, associated with the degeneration of dopamine neurons in PD model mice – an effect which involves enhanced trans-repression of neurotoxic pro-inflammatory genes in microglia and increased transcriptional activation of midbrain dopaminergic (mDA)neurons (Kim et al., 2015). Nurr1 knockout mice even fail to develop dopamine neurons (Zetterström et al., 1997).

       So dopamine-related diseases AD, PD SCZD, Lewy body dementia are accompanied by several NURR1 mutations. (e.g., Chen et al., 2001; Zheng et al., 2003; Chu et al., 2006).

      FOXP2 controls expression of for Alzheimer's disease relevant glycoprotein NCAM1. (Gillian et al., 1994; Todaro et al.,2004 )

      

      Moreover, NCAM1 is a putative target of both RUNX2 (Kuhlwilm et al., 2013) and FOXP2

       (Konopka et al., 2009). In Boeckx and Benítez-Burraco “Globularity and language-readiness: generating new predictions by expanding the set of genes of interest”, the FOXP2 also influences Alzheimer relevant DISC1. Using dual luciferase assays Walker et al. (2012) demonstrated that a region -300 to -177 bp relative to the transcription start site (TSS) contributes positively to DISC1 promoter activity, while a region -982 to -301 bp relative to the TSS confers a repressive effect and inhibition of DISC1 promoter activity and protein expression by forkhead-box P2 (FOXP2). R553H and R328X FOXP2 point mutations found, known from developmental verbal dyspraxia affected families, decreases his inhibition. Further knockdown of DISC1 increases the expression of APP at the cell surface and decreases its internalization. (Shahani et al., 2015)

       Further aging and neurodegeneration relevant FOXP2 targets

       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