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

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.

      Structure and function of FoxP genes is responsible for his function

       Structure of the FoxP2 gene and its isoforms

      The FOXP2 gene is located on chromosome 7 and contains at least 280 (according to some data 603) kb, many introns (about 280,000 non-coding base pairs, according to a publication in 2007 - 603,000 base pairs), 7 exons ( 2145 coding base pairs), but their number is variable. (Zhang et al., 2002;Wright and Hastie, 2007)

       The protein product of the FOXP2 gene consists of 715 amino acids and has the following domains: a highly conserved DNA-binding domain, a 508 to 584 amino acid "winged" helix domain (BHT) and the forkhead box with highly conserved two beta-sheets, three alpha helixes and a helix-turn-helix-motif-wing.

       Structural variations occur between the second and third helix. The polyglutamine-rich regions with the repetitive CAG and CAA sequences show a high mutation rate as well as different length in different taxa. The FOXP2 gene has a zip finger involved in protein-protein interactions and a leucine zipper. The DNA binding in the minor and the major groove to various targets occurs between the third alpha helix (recognition helix) and the second wing of the FOX transcript. (Enard et al., 2002;Kaestner et al., 2000; MacDermot et al., 2005) The hinge loop plays the most important role in the FOXP2 protein binding to the target genes and the mutation P539A changes its form.(Morris et al., 2018)

       Alternative splicing creates different FOXP2 isoforms and causes changes in FOXP2 activity. (Castellano and Downward, 2011). Depending on the tissue and cell type, FOXP2 expression can be started on at least 4 starting points (TSSs). (Bruce and Margolis, 2002; Schroeder and Myers, 2008).

       Regulation of various genes by dimer formation with FOXP genes

      FOXP2 cooperation and FOXP homo- and heterodimers A strong cooperation between FOXP members could be due to the fact that the FOXP2, FOXP1, FOXP3, and FOXP4 are 55-65% identical. A possible explanation for this similarity is proposed by Song et al. in "Genesis of the vertebrate FoxP subfamily member genesis during two ancestral whole genome duplication events" (2016). According to Murugan et al. (2013) decreased FoxP2 expression in the striatal region of adult zebra finches also interferes with their sensitivity to dopaminergic regulation in signalling via D1 receptors in Area-X, they also have co-localized dopamine D1A, D1B and D2 receptors in striatal Foxp2-expressing neurons. Dopamine is considered to be an important neurotransmitter whose deficiency causes some neurodegenerative diseases, e.g. aging relevant Parkinson's disease. This disease is characterized among other things by a washed-out language. It would be interesting to investigate if FOXP2 plays a role in these processes. The FoxP proteins can regulate their target genes in various cellular contexts depending on binding cofactor. Different protein combinations can lead to opposite effects. This could explain why certain tissues might be much more susceptible to the effects of mutations than other tissues. This study opened new perspectives in the regulation of FOXP2 target genes via protein-protein interactions between the FoxP family members, enabling a deeper understanding of the combinatorial control between the FoxP2 and