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

or CAGH44) was mainly associated with important language functions. First, the FOXP2 became known through the work of Anthony Monaco and Svante Pääbo Group at the Institute for Evolutionary Anthropology of the Max Planck Society in Leipzig. They studied the linguistic deficient KE family and found an autosomal dominant missense point mutation in exon 14 of the 7th chromosome (in the 7q31 band guanine was replaced by adenine). This mutation replaced arginine (R) by histidine (H) at the position 553 R553H of the FOXP2 protein and caused an inhibition of the DNA-binding domain and the inoperability of the protein. Other FOXP2 mutations were also observed by dyspraxia patients. (MacDermot et al., 2005; O'Brien et al., 2003; Jiménez-Romero et al., 2016; Becker et al., 2015; Zeesman et al., 2006).

       In 2016 described Tborres-Ruiz et al. a girl with inherited complete chromosomal rearrangement. This rearrangement was accompanied by a fracture proximal and distal to the FOXP2 gene and resulted in cognitive disabilities. The fracture in a new neuroblastoma cell line SK-N-MC led to the decline of FOXP2 and increase of MDFIC-P protein levels. The MDFIC-P gene is localized near FOXP2. The FOXP-2 significance for the childhood apraxia of speech (CAS) and other speech disorders were also described. (Morgan et al., 2017; Kurt et al, 2012)

       The FOXP2 mutations are often accompanied by structural brain changes, so the new multimodal MRI study of an eight-year-old boy (A-II) with a de novo FOXP2 deletion by Liégeois et al. „Early neuroimaging markers of FOXP2 intragenic deletion“ (2016). The researchers described in their work significant bilateral structural abnormalities in the basal ganglia and in hippocampus. In the hippocampus, in the thalamus, in the globus pallidum and in the caudate nucleus a volume reduction was also observed in comparison to the control group of 26 healthy volunteers. The patients showed no detectable functional MRI activity by the repetition of nonsense phrases.

       FOXP2 also plays a role in the visual system (Iwai et al., 2013; Horng et al., 2009), in psychiatric disorders, and in aging dependent frontotemporal degenerative dementia accompanied by speech disorders (Sanjuán et al., 2006; Park et al., 2014; Wang et al, 2016; Bacon and Rappold, 2012; Fisher and Scharff, 2009; Premi et al., 2012; Kumar, et al., 2011).

       FOXP2 is important for brain development and communication in many animal taxa (e.g. songbirds, marine mammals, bats and possibly elephants) which learn to communicate through imitation and whose auditory processing needs to interact with motor control. (Scharff and Haesler, 2005)

       Scharff and Petri (2011) emphasized in „Evo-devo, deep homology and FoxP2: implications for the evolution of speech and language“ that FOXP2 shows different expression cycles in different neuronal subtypes and „the more efforts should be directed at identifying the genomic loci regulating temporal expression differences of FoxP2“.

       Other members of the FOXP2 family show many parallels to FOXP2. (Viscard et al., 2017)

       FOXP2 and Alzheimer

      López-González et al., 2016 described in FOXP2 Expression in Frontotemporal Lobar Degeneration-Tau that reduced mRNA and protein expression of FOXP2 in frontal cortex area 8 in Pick’s disease and in frontotemporal lobar degeneration-tau. This tau degeneration was linked to P301L mutation, that was associated with language impairment in comparison to age-matched controls and cases with parkinsonian variant progressive supranuclear palsy. “Foxp2 mRNA and protein are also reduced with disease progression in the somatosensory cortex in transgenic mice bearing the P301S mutation in MAPT when compared with wild-type littermates. These findings support the presence of FOXP2 expression abnormalities in sporadic and familial frontotemporal degeneration tauopathies.” (López-González et al., 2016, p.1)

      Padovani et al. investigated 2010 in „The speech and language FOXP2 gene modulates the phenotype of frontotemporal lobar degeneration“ the influence of genetic variations within FOXP2 in neurological disorders and how FOXP2 polymorphisms influences frontotemporal lobar degeneration. After neuropsychological examination as well as brain imaging of two-hundred ten FTLD patients and in 200 age-matched healthy controls the researchers evaluated four FOXP2 polymorphisms: rs2396753, rs1456031, rs17137124 and rs1852469 they observed no significant differences in SPECT images of the four FOXP2 polymorphisms in genotype distribution and allele frequency between FTLD and controls, in the same time they reported a significant and specific association between rs1456031 TT and rs17137124 TT genotypes and verbal fluency scores and an addictive effect of two polymorphisms. Afterwards they computed the number of observations over time and obtained 391 comparable results that showed: FTLD patients carrying at-risk polymorphisms have greater hypoperfusion in the frontal areas, namely the left inferior frontal gyrus, and putamen, compared to the non-carriers. Genetic variations within FOXP2 modulate FTLD presentation when disease is overt, affecting language performances and leading to hypoperfusion in language-associated brain areas.

      Di Meco et al. proposed 2019 in „Gestational high fat diet protects 3xTg offspring from memory impairments, synaptic dysfunction, and brain pathology“ new insights in maternal history for sporadic Alzheimer’s disease (AD) and the possibility of susceptibility modulation to AD via gestational high fat diet. Triple transgenic dams (human PS1, human MAPT and KM670/671NL)

       were fed with high fat diet: 42% calories from fat or regular chow 13% calories from fat throughout 3 weeks gestation. This study showed how gestational high fat diet attenuated memory decline, synaptic dysfunction, amyloid-β and tau neuropathology (decrease in the levels of Aβ1–40 and Aβ1–42) in the offspring by transcriptional regulation of BACE-1, CDK5, and tau gene expression via the upregulation of FOXP2 repressor. To proof that FOXP2 effects on tau,

       CDK5 and BACE-1 the researchers exposed APPswe mutant N2A cells to FOXP2-GFP plasmid and measured tau, FOXP2, CDK5 and BACE-1 protein and mRNA levels 24 hours after, wich were decreased, but lower APP level was not observed. Behavioral impairments could be improved under and electrophysiology of 3TG hippocampal slices showed higher excitatory postsynaptic potentials as well as increasing strength of stimulus intensities. Longterm potentiation in the CA1 region of the hippocampus and paired pulse facilitation were measured and showed partial restoration of the

       fEPSP in 3TG HF, also of neuronal plasticity and memory. So gestational high fat diet significantly decreases tau aggregation-prone isoforms level, soluble tau level as well as of its phosphorylated isoforms and protects this way offspring from later AD.

      There is many evidences about indirect influence of FOXP2 on neurodegenerative diseases, so:

      FOXP2 controls expression of for Alzheimer's disease relevant RELN (Adam et al.,2016)

      Seripa et al. described 2012 in „The RELN locus in Alzheimer's disease. “ serine protease, encoded by the RELN gene, as part of in AD involved apoE pathways. The researchers investigated three polymorphisms in the RELN locus, i.e., a triplet tandem repeat in the 5'UTR and two single-nucleotide polymorphisms (SNPs) rs607755 and rs2229874, located in the exon 6 splice-junction and in the exon 50 coding region. The analysis of 223 sporadic AD patients 181 controls. There was no significant differences in rs2229874 but in 5'UTR and rs607755 genotypes, in females and not in males (even if APOE genotypes were adjustment). So RELN gene variants may effect AD pathogenesis of, especially in females.

      In“ Reelin depletion is an early phenomenon of Alzheimer's pathology“ 2012 Herring et al. examined the expression profile of with Alzheimer's disease associated “RELN and its downstream signalling members APOER2, VLDLR, and DAB1 in AD-vulnerable regions of transgenic and wildtype mice as well as in AD patients and controls across disease stages and/or aging..”(Herring et al., 2012, p.1) Their results showed that “AD pathology and aging are associated with perturbation of the RELN pathway in a species-, region-, and molecule-specific manner” and the “depletion of RELN, but not its downstream signalling molecules, is detectable long before the onset of amyloid-β pathology in the murine hippocampus and in a pre-clinical AD stage in the human frontal cortex. This early event hints at a possible causative role of RELN decline in the precipitation of AD pathology and supports RELN's potential as a pre-clinical marker for AD.” (Herring et al., 2012, p.1)

       FOXP-2 affects NCAM1, VLDLR and other target genes in the nervous system