REST/NRSF-induced changes of ChAT protein expression in the neocortex and hippocampus of the 3xTg-AD mouse model for Alzheimer's disease

Orta‐Salazar, Erika; Aguilar-Vázquez, Azucena; Martínez-Coria, Hilda; Anda, Silje; Rivera-Cervantes, M.C.; Beas‐Zárate, Carlos; Feria‐Velasco, Alfredo; Dı́az-Cintra, Sofı́a

doi:10.1016/j.lfs.2014.09.013

Cited by 30 publications

(19 citation statements)

References 32 publications

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“…REST expression is induced during normal brain aging and its activation generally entails neuroprotection by downregulating targets involved in cell death . However, transcription of REST is markedly reduced in AD‐affected neuronal populations . Moreover, REST increases transcription of genes related to neurotransmission in the early stages of AD.…”

Section: Discussionmentioning

confidence: 99%

Impaired hypoxic tolerance in APP23 mice: a dysregulation of neuroprotective globin levels

et al. 2017

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Although neuroglobin confers neuroprotection against Alzheimer's disease (AD) pathology, its expression becomes downregulated in late‐stage AD. Here, we provide evidence that indicates that this decrease is associated with the AD‐linked angiopathy. While wild‐type mice of different ages show upregulated cerebral neuroglobin expression upon whole‐body hypoxia, APP23 mice exhibit decreased cerebral transcription of neuroglobin. Interestingly, transcription of cytoglobin, whose involvement in amyloid pathology still needs to be elucidated, follows a similar pattern. To further unravel the underlying mechanism, we examined the expression levels of the RE‐1‐silencing transcription factor (REST/NRSF) after identifying a recognition site for it in the regulatory region of both globins. Neuroglobin‐cytoglobin‐REST/NRSF expression correlations are detected mainly in the cortex. This raises the possibility of REST/NRSF being an upstream regulator of these globins.

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Section: Discussionmentioning

confidence: 99%

Impaired hypoxic tolerance in APP23 mice: a dysregulation of neuroprotective globin levels

et al. 2017

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“…Furthermore, Varghese et al (21) demonstrated that expression of NRSF/REST was reduced in uterine fibroids (leiomyomas). A decreased NRSF/REST expression profile was also detected in human brain tissue from patients with dementia and in the brain tissue from an Alzheimer's disease mouse model (26,27).…”

Section: Discussionmentioning

confidence: 85%

“…For example, Conti et al (14) also reported that in normal human tissue, NRSF/REST immunoreactivity was detected in the cytoplasm of selected neurons. Furthermore, Orta-Salazar et al (27) reported that in the hippocampus of a 3xTg-AD mouse (a mouse model of Alzheimer's disease), the nuclei and cytoplasm were NRSF/REST-positive. Additionally, these mice exhibited decreased cytoplasmic and increased nuclear NRSF/REST staining compared with control mice, which was indicated to be associated with the degeneration observed in Alzheimer's disease.…”

Section: Discussionmentioning

confidence: 99%

NRSF/REST levels are decreased in cholangiocellular carcinoma but not hepatocellular carcinoma compared with normal liver tissues: A tissue microarray study

Zhang

et al. 2018

Oncol Lett

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Abstract. The transcription factor neuron-restrictive silencer factor (NRSF), also termed repressor element 1-silencing transcription factor (REST), has been previously demonstrated to repress the expression of neuronal genes in non-neuronal cells, facilitating the controlled development and organization of nerve tissue. However, previous studies have reported NRSF/REST to be upregulated or downregulated in multiple types of carcinoma. Liver diseases are a major global health concern, with cirrhosis and liver carcinoma among the most common causes of mortality worldwide. A previous study demonstrated that there were >400 NRSF/REST target genes in mouse liver cells; however, the expression profile of NRSF/REST in human liver disease remains unclear. The present study examined NRSF/REST expression in human normal and liver carcinoma samples using tissue microarray immunohistochemistry. The results demonstrated that in normal liver tissues, NRSF/REST can be detected in the cytoplasm and nuclei of the cell; whereas in the liver carcinoma tissue, NRSF/REST is only detected in the cytoplasm. Furthermore, the number of samples with high levels of NRSF/REST was significantly lower in cholangiocellular carcinoma samples compared with normal tissues. Additionally, no detectable sex-or age-associated differences were identified in NRSF/REST expression among all the tissues examined. In conclusion, the results of the present study revealed nuclear loss of NRSF/REST in hepatic carcinomas and decreased expression of NRSF/REST in cholangiocellular carcinoma, indicating that the cytoplasmic translocation of NRSF/REST may be involved in liver tumorigenesis. A low expression level of NRSF/REST may be a novel biomarker for cholangiocellular carcinoma. IntroductionNeuron-restrictive silencer factor (NRSF), also termed repressor element 1-silencing transcription factor (REST), is a zinc-finger transcription factor and an important regulator of neural genes (1). Chong et al (2) first reported that NRSF/REST is a silencer protein that reduces the expression of sodium channel genes in neurons. A previous study demonstrated that NRSF/REST is an important regulator of neurogenesis in vitro and in vivo. For example, downregulation of NRSF/REST in embryonic stem cells induces neuronal lineage differentiation (3), and knockdown of NRSF/REST in cultured neural stem cells induces the expression of pro-neuronal genes, including neuronal differentiation 1, neuron-specific class III β-tubulin and doublecortin (4). In Xenopus and chicken embryos, NRSF/REST inactivation induces abnormal neurogenesis and inhibits the repression of neuronal tubulin and several other neuronal target genes (5,6). Additionally, NRSF/REST overexpression represses the expression of neuronal genes, including N-tubulin and neuronal cell adhesion molecule (7).Numerous studies have investigated the expression and, to a lesser extent, the function of NRSF/REST in tumors of the nervous system (8-15). Certain tumors, including neuroblastoma, share a number of biological propert...

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“…Studies of G-protein-coupled receptors have not included details about REST increases and gene target inhibition ( Kim et al, 2004 ; Formisano et al, 2007 ; Henriksson et al, 2014 ). In contrast, studies with kainate, a glutamatergic agent that is active on channel receptors, that were first performed by Palm et al (1998) and then by other groups (see, among others, Calderone et al, 2003 ; Spencer et al, 2006 ; Formisano et al, 2007 ; McClelland et al, 2011a , 2014 ; Orta-Salazar et al, 2014 ; Rivera-Cervantes et al, 2015 ), revealed the induction of REST upregulation in vivo in hippocampal and cortical neurons. Analogous results induced by prolonged treatment with the same agent were obtained in primary cultures of rat hippocampal CA1 neurons ( Spencer et al, 2006 ; Lau and Tymianski, 2010 ; Ortuño-Sahagún et al, 2014 ; Rivera-Cervantes et al, 2015 ) and in brain slices prepared ex vivo ( Calderone et al, 2003 ; McClelland et al, 2011a ).…”

Section: Physiologymentioning

confidence: 99%

The Transcription Repressor REST in Adult Neurons: Physiology, Pathology, and Diseases

Baldelli

Meldolesi

2015

eneuro

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REST [RE1-silencing transcription factor (also called neuron-restrictive silencer factor)] is known to repress thousands of possible target genes, many of which are neuron specific. To date, REST repression has been investigated mostly in stem cells and differentiating neurons. Current evidence demonstrates its importance in adult neurons as well. Low levels of REST, which are acquired during differentiation, govern the expression of specific neuronal phenotypes. REST-dependent genes encode important targets, including transcription factors, transmitter release proteins, voltage-dependent and receptor channels, and signaling proteins. Additional neuronal properties depend on miRNAs expressed reciprocally to REST and on specific splicing factors. In adult neurons, REST levels are not always low. Increases occur during aging in healthy humans. Moreover, extensive evidence demonstrates that prolonged stimulation with various agents induces REST increases, which are associated with the repression of neuron-specific genes with appropriate, intermediate REST binding affinity. Whether neuronal increases in REST are protective or detrimental remains a subject of debate. Examples of CA1 hippocampal neuron protection upon depolarization, and of neurodegeneration upon glutamate treatment and hypoxia have been reported. REST participation in psychiatric and neurological diseases has been shown, especially in Alzheimer’s disease and Huntington’s disease, as well as epilepsy. Distinct, complex roles of the repressor in these different diseases have emerged. In conclusion, REST is certainly very important in a large number of conditions. We suggest that the conflicting results reported for the role of REST in physiology, pathology, and disease depend on its complex, direct, and indirect actions on many gene targets and on the diverse approaches used during the investigations.

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REST/NRSF-induced changes of ChAT protein expression in the neocortex and hippocampus of the 3xTg-AD mouse model for Alzheimer's disease

Cited by 30 publications

References 32 publications

Impaired hypoxic tolerance in APP23 mice: a dysregulation of neuroprotective globin levels

Impaired hypoxic tolerance in APP23 mice: a dysregulation of neuroprotective globin levels

NRSF/REST levels are decreased in cholangiocellular carcinoma but not hepatocellular carcinoma compared with normal liver tissues: A tissue microarray study

The Transcription Repressor REST in Adult Neurons: Physiology, Pathology, and Diseases

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