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

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      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).