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Novel roles of non-coding brain RNAs in health and disease
Hermona Soreq
Frontiers in Molecular Neuroscience , 2014, DOI: 10.3389/fnmol.2014.00055
Abstract: Non-coding RNAs (ncRNAs), and in particular microRNAs (miRNAs) are rapidly becoming the focus of research interest in numerous basic and translational fields, and their importance for many aspects in brain functioning reveals novel roles and merits special discussion. The wide-scope, multi-targeted and highly efficient manner of ncRNA regulatory activities draws attention to this topic by many, but the available research tools and experimental protocols are still insufficient, and their importance for many aspects in brain functioning keeps changing. Much of the research effort in this field has initially been devoted to cancer research, but the regulatory role of ncRNAs is considered global. Consequently, molecular neuroscientists picked it up as well, although the brain presents special challenges for ncRNA and miRNA research. To reflect the rapid recent development of ncRNA and miRNA research in the nervous system, this Research Topic eBook is focused on the search for and exploration of those ncRNAs and miRNAs whose activities modulate the multi-leveled functions of the eukaryotic brain in health and disease. It strives to cover the state of the art expertise and describe novel roles for known and recently identified ncRNAs and miRNAs and cover experimental approaches for identifying and establishing ncRNA-target relationships, reports of the affected pathways, inherited and acquired changes in ncRNA functioning and the use of ncRNA mimics and blockade tools for interference with their functions in health and disease. This eBook covers several key topics of interest in the molecular neuroscience field that try to bridge the gap between ncRNAs, miRNAs and the wider research community. As researchers, we are interested in advancing this field for the improvement of both basic and translational studies aimed at progressing towards better human health and wellbeing. Therefore, this volume is opened by a review contributed by the Gerhard Schratt group that presents a comprehensive characterization of the nuclear miRNA repertoire of post-mitotic neurons (Khudayberdiev et al., 2013). This is followed by a thorough discussion of the flexibility and stability of miRNAs in brain development and function that was written by the Christophe Beclin group (Follert et al., 2014) and by insights on the functional interactions between miRNAs and copy number variations in the aging brain contributed by the Ronald Bontrop group (Persengiev et al., 2013). Yet other authors focused their articles on particular neuronal roles of specific miRNAs. Thus, Alexander Murashov
Cholinesterase-Targeting microRNAs Identified in silico Affect Specific Biological Processes
Hermona Soreq
Frontiers in Molecular Neuroscience , 2011, DOI: 10.3389/fnmol.2011.00028
Abstract: MicroRNAs (miRs) have emerged as important gene silencers affecting many target mRNAs. Here, we report the identification of 244 miRs that target the 3′-untranslated regions of different cholinesterase transcripts: 116 for butyrylcholinesterase (BChE), 47 for the synaptic acetylcholinesterase (AChE-S) splice variant, and 81 for the normally rare splice variant AChE-R. Of these, 11 and 6 miRs target both AChE-S and AChE-R, and AChE-R and BChE transcripts, respectively. BChE and AChE-S showed no overlapping miRs, attesting to their distinct modes of miR regulation. Generally, miRs can suppress a number of targets; thereby controlling an entire battery of functions. To evaluate the importance of the cholinesterase-targeted miRs in other specific biological processes we searched for their other experimentally validated target transcripts and analyzed the gene ontology enriched biological processes these transcripts are involved in. Interestingly, a number of the resulting categories are also related to cholinesterases. They include, for BChE, response to glucocorticoid stimulus, and for AChE, response to wounding and two child terms of neuron development: regulation of axonogenesis and regulation of dendrite morphogenesis. Importantly, all of the AChE-targeting miRs found to be related to these selected processes were directed against the normally rare AChE-R splice variant, with three of them, including the neurogenesis regulator miR-132, also directed against AChE-S. Our findings point at the AChE-R splice variant as particularly susceptible to miR regulation, highlight those biological functions of cholinesterases that are likely to be subject to miR post-transcriptional control, demonstrate the selectivity of miRs in regulating specific biological processes, and open new venues for targeted interference with these specific processes.
Predicted overlapping microRNA regulators of acetylcholine packaging and degradation in neuroinflammation-related disorders
Bettina Nadorp,Hermona Soreq
Frontiers in Molecular Neuroscience , 2014, DOI: 10.3389/fnmol.2014.00009
Abstract: MicroRNAs (miRNAs) can notably control many targets each and regulate entire cellular pathways, but whether miRNAs can regulate complete neurotransmission processes is largely unknown. Here, we report that miRNAs with complementary sequence motifs to the key genes involved in acetylcholine (ACh) synthesis and/or packaging show massive overlap with those regulating ACh degradation. To address this topic, we first searched for miRNAs that could target the 3′-untranslated regions of the choline acetyltransferase (ChAT) gene that controls ACh synthesis; the vesicular ACh transporter (VAChT), encoded from an intron in the ChAT gene and the ACh hydrolyzing genes acetyl- and/or butyrylcholinesterase (AChE, BChE). Intriguingly, we found that many of the miRNAs targeting these genes are primate-specific, and that changes in their levels associate with inflammation, anxiety, brain damage, cardiac, neurodegenerative, or pain-related syndromes. To validate the in vivo relevance of this dual interaction, we selected the evolutionarily conserved miR-186, which targets both the stress-inducible soluble “readthrough” variant AChE-R and the major peripheral cholinesterase BChE. We exposed mice to predator scent stress and searched for potential associations between consequent changes in their miR-186, AChE-R, and BChE levels. Both intestinal miR-186 as well as BChE and AChE-R activities were conspicuously elevated 1 week post-exposure, highlighting the previously unknown involvement of miR-186 and BChE in psychological stress responses. Overlapping miRNA regulation emerges from our findings as a recently evolved surveillance mechanism over cholinergic neurotransmission in health and disease; and the corresponding miRNA details and disease relevance may serve as a useful resource for studying the molecular mechanisms underlying this surveillance.
Acetylcholinesterase: old questions and new developments
Karl Tsim,Hermona Soreq
Frontiers in Molecular Neuroscience , 2013, DOI: 10.3389/fnmol.2012.00101
Emerging bioinformatics approaches for analysis of NGS-derived coding and non-coding RNAs in neurodegenerative diseases
Alessandro Guffanti,Alon Simchovitz,Hermona Soreq
Frontiers in Cellular Neuroscience , 2014, DOI: 10.3389/fncel.2014.00089
Abstract: Neurodegenerative diseases in general and specifically late-onset Alzheimer’s disease (LOAD) involve a genetically complex and largely obscure ensemble of causative and risk factors accompanied by complex feedback responses. The advent of “high-throughput” transcriptome investigation technologies such as microarray and deep sequencing is increasingly being combined with sophisticated statistical and bioinformatics analysis methods complemented by knowledge-based approaches such as Bayesian Networks or network and graph analyses. Together, such “integrative” studies are beginning to identify co-regulated gene networks linked with biological pathways and potentially modulating disease predisposition, outcome, and progression. Specifically, bioinformatics analyses of integrated microarray and genotyping data in cases and controls reveal changes in gene expression of both protein-coding and small and long regulatory RNAs; highlight relevant quantitative transcriptional differences between LOAD and non-demented control brains and demonstrate reconfiguration of functionally meaningful molecular interaction structures in LOAD. These may be measured as changes in connectivity in “hub nodes” of relevant gene networks (Zhang et al., 2013). We illustrate here the open analytical questions in the transcriptome investigation of neurodegenerative disease studies, proposing “ad hoc” strategies for the evaluation of differential gene expression and hints for a simple analysis of the non-coding RNA (ncRNA) part of such datasets. We then survey the emerging role of long ncRNAs (lncRNAs) in the healthy and diseased brain transcriptome and describe the main current methods for computational modeling of gene networks. We propose accessible modular and pathway-oriented methods and guidelines for bioinformatics investigations of whole transcriptome next generation sequencing datasets. We finally present methods and databases for functional interpretations of lncRNAs and propose a simple heuristic approach to visualize and represent physical and functional interactions of the coding and non-coding components of the transcriptome. Integrating in a functional and integrated vision coding and ncRNA analyses is of utmost importance for current and future analyses of neurodegenerative transcriptomes.
Hippocampal Lipocalin 2: an emotional link between neurons and glia
Oliver von Bohlen und Halbach,Hermona Soreq
Frontiers in Cellular Neuroscience , 2013, DOI: 10.3389/fncel.2013.00132
Stressing hematopoiesis and immunity: an acetylcholinesterase window into nervous and immune system interactions
Adi Gilboa-Geffen,Hermona Soreq
Frontiers in Molecular Neuroscience , 2012, DOI: 10.3389/fnmol.2012.00030
Abstract: Hematopoietic stem cells (HSCs) differentiate and generate all blood cell lineages while maintaining self-renewal ability throughout life. Systemic responses to stressful insults, either psychological or physical exert both stimulating and down-regulating effects on these dynamic members of the immune system. Stress-facilitated division and re-oriented differentiation of progenitor cells modifies hematopoietic cell type composition, while enhancing cytokine production and promoting inflammation. Inversely, stress-induced increases in the neurotransmitter acetylcholine (ACh) act to mitigate inflammatory response and regain homeostasis. This signaling process is terminated when ACh is hydrolyzed by acetylcholinesterase (AChE). Alternative splicing, which is stress-modified, changes the composition of AChE variants, modifying their terminal sequences, susceptibility for microRNA suppression, and sub-cellular localizations. Intriguingly, the effects of stress and AChE variants on hematopoietic development and inflammation in health and disease are both subject to small molecule as well as oligonucleotide-mediated manipulations in vitro and in vivo. The therapeutic agents can thus be targeted to the enzyme protein, its encoding mRNA transcripts, or the regulator microRNA-132, opening new venues for therapeutic interference with multiple nervous and immune system diseases.
Serum AChE Activities Predict Exercise Heart Rate Parameters of Asymptomatic Individuals  [PDF]
Canaani Jonathan, Shenhar-Tsarfaty Shani, Weiskopf Nir, Yakobi Reut, Ben Assayag Einor, Berliner Shlomo, Soreq Hermona
Neuroscience & Medicine (NM) , 2010, DOI: 10.4236/nm.2010.12007
Abstract: Background specific heart rate parameters notably associate with variable risks of cardiovascular disease and mortal-ity, however, to date there are no readily available blood tests associated with these parameters. Because of the estab-lished parasympathetic contributions towards cardiac regulation, we challenged the working hypothesis that serum acetylcholinesterase (AChE) activity is involved. Methods A total of 403 Healthy men and women were included in the study and underwent treadmill exercise testing. Prior to exercise testing the subject’s serum AChE activity levels were assessed by measuring rates of acetylthiocholine hydrolysis. Results In male subjects AChE activity was positively cor-related to resting heart rate (r = 0.210, p = 0.001). Complementing this observation, AChE activity was negatively correlated to the exercise-induced heart rate increase (r = –0.181, p = 0.005) and to heart rate recovery at 1, 2 and 5 minutes following cessation of exercise (r = –0.150, p = 0.022; r = –0.157, p = 0.016; r = –0.176, p = 0.008 respec-tively). This indicated that lower than average AChE activities, which presumably reflect increased peripheral ACh levels, might be correlated to favorable heart rate parameters. Similar observations were made in female subjects, ex-cept for lack of correlation to their resting heart rate. Additionally, we observed that we were able to stratify subjects into two groups of significantly different AChE activity (p = 0.001) based on a cut point of heart rate recovery below 20 beats one minute after cessation of exercise. Conclusion In asymptomatic individuals lower than average AChE activity is associated with favorable indices of exercise-inducible heart rate increase as well as heart rate recovery. Future studies will be needed to evaluate the added prognostic significance gained by implementing this marker into routine practice.
Acetylcholinesterase loosens the brain's cholinergic anti-inflammatory response and promotes epileptogenesis
Yehudit Gnatek,Yael Goll,Naim Najami,Hermona Soreq,Alon Friedman
Frontiers in Molecular Neuroscience , 2012, DOI: 10.3389/fnmol.2012.00066
Abstract: Recent studies show a key role of brain inflammation in epilepsy. However, the mechanisms controlling brain immune response are only partly understood. In the periphery, acetylcholine (ACh) release by the vagus nerve restrains inflammation by inhibiting the activation of leukocytes. Recent reports suggested a similar anti-inflammatory effect for ACh in the brain. Since brain cholinergic dysfunctions are documented in epileptic animals, we explored changes in brain cholinergic gene expression and associated immune response during pilocarpine-induced epileptogenesis. Levels of acetylcholinesterase (AChE) and inflammatory markers were measured using real-time RT-PCR, in-situ hybridization and immunostaining in wild type (WT) and transgenic mice over-expressing the “synaptic” splice variant AChE-S (TgS). One month following pilocarpine, mice were video-monitored for spontaneous seizures. To test directly the effect of ACh on the brain's innate immune response, cytokines expression levels were measured in acute brain slices treated with cholinergic agents. We report a robust up-regulation of AChE as early as 48 h following pilocarpine-induced status epilepticus (SE). AChE was expressed in hippocampal neurons, microglia, and endothelial cells but rarely in astrocytes. TgS mice overexpressing AChE showed constitutive increased microglial activation, elevated levels of pro-inflammatory cytokines 48 h after SE and accelerated epileptogenesis compared to their WT counterparts. Finally we show a direct, muscarine-receptor dependant, nicotine-receptor independent anti-inflammatory effect of ACh in brain slices maintained ex vivo. Our work demonstrates for the first time, that ACh directly suppresses brain innate immune response and that AChE up-regulation after SE is associated with enhanced immune response, facilitating the epileptogenic process. Our results highlight the cholinergic system as a potential new target for the prevention of seizures and epilepsy.
Long Non-Coding RNA and Alternative Splicing Modulations in Parkinson's Leukocytes Identified by RNA Sequencing
Lilach Soreq,Alessandro Guffanti,Nathan Salomonis,Alon Simchovitz,Zvi Israel,Hagai Bergman,Hermona Soreq
PLOS Computational Biology , 2014, DOI: doi/10.1371/journal.pcbi.1003517
Abstract: The continuously prolonged human lifespan is accompanied by increase in neurodegenerative diseases incidence, calling for the development of inexpensive blood-based diagnostics. Analyzing blood cell transcripts by RNA-Seq is a robust means to identify novel biomarkers that rapidly becomes a commonplace. However, there is lack of tools to discover novel exons, junctions and splicing events and to precisely and sensitively assess differential splicing through RNA-Seq data analysis and across RNA-Seq platforms. Here, we present a new and comprehensive computational workflow for whole-transcriptome RNA-Seq analysis, using an updated version of the software AltAnalyze, to identify both known and novel high-confidence alternative splicing events, and to integrate them with both protein-domains and microRNA binding annotations. We applied the novel workflow on RNA-Seq data from Parkinson's disease (PD) patients' leukocytes pre- and post- Deep Brain Stimulation (DBS) treatment and compared to healthy controls. Disease-mediated changes included decreased usage of alternative promoters and N-termini, 5′-end variations and mutually-exclusive exons. The PD regulated FUS and HNRNP A/B included prion-like domains regulated regions. We also present here a workflow to identify and analyze long non-coding RNAs (lncRNAs) via RNA-Seq data. We identified reduced lncRNA expression and selective PD-induced changes in 13 of over 6,000 detected leukocyte lncRNAs, four of which were inversely altered post-DBS. These included the U1 spliceosomal lncRNA and RP11-462G22.1, each entailing sequence complementarity to numerous microRNAs. Analysis of RNA-Seq from PD and unaffected controls brains revealed over 7,000 brain-expressed lncRNAs, of which 3,495 were co-expressed in the leukocytes including U1, which showed both leukocyte and brain increases. Furthermore, qRT-PCR validations confirmed these co-increases in PD leukocytes and two brain regions, the amygdala and substantia-nigra, compared to controls. This novel workflow allows deep multi-level inspection of RNA-Seq datasets and provides a comprehensive new resource for understanding disease transcriptome modifications in PD and other neurodegenerative diseases.
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