Читать книгу Influence of FOX genes on aging and aging-associated diseases - Elena Tschumak - Страница 9

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

FOXP2 controls expression of for 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)