Influence of FOX genes on aging and aging-associated diseases. Elena Tschumak
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Название: Influence of FOX genes on aging and aging-associated diseases
Автор: Elena Tschumak
Издательство: Bookwire
Жанр: Медицина
isbn: 9783754131572
isbn:
Bahn et al. (2019) showed in „NRF2/ARE pathway negatively regulates BACE1 expression and ameliorates cognitive deficits in mouse Alzheimer's models“ BACE1 as the rate limiting Aβ generation enzyme. AD is accompanied by BACE1 and a BACE1 mRNA-stabilizing antisense RNA elevation. NRF2/NFE2L2 represses the BACE1 and BACE1-AS-expression via ARE promoters binding, independent of redox regulation. Also NRF2 improves cognitive deficits in animal models of AD, so the authors regard NRF2 as a possible key factor in prevention of early pathogenic process in AD.
KEAP1
Kerr et al. (2017) associate in „Direct Keap1-Nrf2 disruption as a potential therapeutic target for Alzheimer's disease“ Nrf2 with cell protection and an attractive therapeutic target for the prevention of neurodegenerative diseases, including Alzheimer’s disease (AD), provided in vivo evidence that specific inhibition of negative regulator of Nrf2 Keap1 can prevent neuronal toxicity in response to the AD-initiating Aβ42 peptide. Lithium, an inhibitor of the Nrf2 suppressor GSK-3, prevented Aβ42 toxicity in Nrf2 independent way.
JAK / STAT signalling
Nevado-Holgado et al. published 2019 „Genetic and Real-World Clinical Data, Combined with Empirical Validation, Nominate Jak-Stat Signaling as a Target for Alzheimer's Disease Therapeutic Developmen“, where they combined GWAS results with the current knowledge of molecular pathways, real-world clinical data from six million patients, RNA expression across tissues from AD patients and rodent models and showed that the degree of comorbidity of these diseases with AD correlates with the strength of their genetic association with molecular participants in the Janus kinases/signal transducer and activator of transcription pathway. They demonstrated Aβ induction by JAK-STAT anomalies and identified these genes as a potential target for therapeutic approach.
SERPINH1
Aβ and cytokines, involved in microglial activation, play a crucial role in neuroinflammation and AD. Yoo et al. published 2015 „ Amyloid-beta-activated human microglial cells through ER-resident proteins“ . They performed a proteomic analysis of Aβ-stimulated human microglial cells by stable isotope labelling with amino acids in cell culture combined with LC-MS/MS and clarified ER-resident proteins-level of PDIA6, PDIA3, PPIB and SERPINH1 was altered by 1.5 fold or greater. The researchers suggested that ER proteins play an essential role in human microglial activation by Aβ and could be important therapeutic targets for treatment of AD.
Ezrin-Radixin-Moesin complex.
α-secretases cleave the amyloid precursor protein to neuroprotective soluble APP ectodomain. Darmellah et al. (2012) show in „ Ezrin/radixin/moesin are required for the purinergic P2X7 receptor (P2X7R)-dependent processing of the amyloid precursor protein“ that the activation of ezrin, radixin, and moesin proteins is required for the P2X7R-dependent proteolytic processing of APP leading to sAPPα release and the ERM down-regulation via siRNA blocked it and P2X7R stimulation triggered its phosphorylation. Ezrin must translocate to the plasma membrane to interact with P2X7R and enzymes Rho kinase and the MAPK modules ERK1/2 and JNK act upstream of ERM, whereas a PI3K activity is triggered downstream.
Vega et al. (2018) also demonstrated in „Ezrin Expression is Increased During Disease Progression in a Tauopathy 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 СКАЧАТЬ