scholarly journals Regulatory Mechanisms of the RNA Modification m6A and Significance in Brain Function in Health and Disease

2021 ◽  
Vol 15 ◽  
Author(s):  
Justine Mathoux ◽  
David C. Henshall ◽  
Gary P. Brennan
Keyword(s):  
Neuronal Development ◽  
Regulatory Mechanisms ◽  
Brain Diseases ◽  
Rna Modification ◽  
Additional Layer ◽  
Health And Disease ◽  
The Stability ◽  
Almost All ◽  
And Function

RNA modifications have emerged as an additional layer of regulatory complexity governing the function of almost all species of RNA. N6-methyladenosine (m6A), the addition of methyl groups to adenine residues, is the most abundant and well understood RNA modification. The current review discusses the regulatory mechanisms governing m6A, how this influences neuronal development and function and how aberrant m6A signaling may contribute to neurological disease. M6A is known to regulate the stability of mRNA, the processing of microRNAs and function/processing of tRNAs among other roles. The development of antibodies against m6A has facilitated the application of next generation sequencing to profile methylated RNAs in both health and disease contexts, revealing the extent of this transcriptomic modification. The mechanisms by which m6A is deposited, processed, and potentially removed are increasingly understood. Writer enzymes include METTL3 and METTL14 while YTHDC1 and YTHDF1 are key reader proteins, which recognize and bind the m6A mark. Finally, FTO and ALKBH5 have been identified as potential erasers of m6A, although there in vivo activity and the dynamic nature of this modification requires further study. M6A is enriched in the brain and has emerged as a key regulator of neuronal activity and function in processes including neurodevelopment, learning and memory, synaptic plasticity, and the stress response. Changes to m6A have recently been linked with Schizophrenia and Alzheimer disease. Elucidating the functional consequences of m6A changes in these and other brain diseases may lead to novel insight into disease pathomechanisms, molecular biomarkers and novel therapeutic targets.

scholarly journals DBC1 (Deleted in Breast Cancer 1) modulates the stability and function of the nuclear receptor Rev-erbα

2013 ◽  
Vol 451 (3) ◽  
pp. 453-461 ◽  
Author(s):  
Claudia C. S. Chini ◽  
Carlos Escande ◽  
Veronica Nin ◽  
Eduardo N. Chini
Keyword(s):  
Breast Cancer ◽  
Nuclear Receptor ◽  
Clock Genes ◽  
Mrna Levels ◽  
Protein Levels ◽  
The Stability ◽  
And Function ◽  
Interfering Rna ◽  
In Cells

The nuclear receptor Rev-erbα has been implicated as a major regulator of the circadian clock and integrates circadian rhythm and metabolism. Rev-erbα controls circadian oscillations of several clock genes and Rev-erbα protein degradation is important for maintenance of the circadian oscillations and also for adipocyte differentiation. Elucidating the mechanisms that regulate Rev-erbα stability is essential for our understanding of these processes. In the present paper, we report that the protein DBC1 (Deleted in Breast Cancer 1) is a novel regulator of Rev-erbα. Rev-erbα and DBC1 interact in cells and in vivo, and DBC1 modulates the Rev-erbα repressor function. Depletion of DBC1 by siRNA (small interfering RNA) in cells or in DBC1-KO (knockout) mice produced a marked decrease in Rev-erbα protein levels, but not in mRNA levels. In contrast, DBC1 overexpression significantly enhanced Rev-erbα protein stability by preventing its ubiquitination and degradation. The regulation of Rev-erbα protein levels and function by DBC1 depends on both the N-terminal and C-terminal domains of DBC1. More importantly, in cells depleted of DBC1, there was a dramatic decrease in circadian oscillations of both Rev-erbα and BMAL1. In summary, our data identify DBC1 as an important regulator of the circadian receptor Rev-erbα and proposes that Rev-erbα could be involved in mediating some of the physiological effects of DBC1.

scholarly journals STEM-17. NOT ALL GBM STEM CELLS ARE EQUAL: IMPLICATIONS FOR RESEARCH AND THERAPY

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii199-ii200
Author(s):  
Luciano Galdieri ◽  
Arijita Jash ◽  
Olga Malkova ◽  
Diane Mao ◽  
Jian Campian ◽  
...  
Keyword(s):  
Stem Cells ◽  
Phenotypic Diversity ◽  
Treatment Resistance ◽  
Surface Markers ◽  
Mass Cytometry ◽  
Pathway Activation ◽  
Almost All ◽  
And Function ◽  
Activation Status

Abstract Glioblastoma (GBM) kills almost all patients within 2 years. A subpopulation of cells, GBM stem cells (GSCs), contributes to treatment resistance and recurrence. A major therapeutic goal is to kill GSCs, but no targeted therapy yet exists. Since their discovery, GSCs have been isolated using single surface markers, such as CD15, CD44, CD133, and a-6 integrin. It remains unknown how these single surface marker-defined GSC populations compare to each other in terms of signal transduction and function and whether expression of different combinations of these markers is associated with distinct phenotypes. Using mass cytometry and fresh operating room specimens, we found that 15 distinct GSC subpopulations exist in vivo and they differ in their MEK/ERK, WNT, and AKT pathway activation status. In culture, some subpopulations were lost and previously undetectable ones materialized. GSCs highly expressing all four surface markers had the greatest self-renewal capacity and in vivo tumorigenicity as well as the strongest WNT pathway activation. This work highlights the signaling and phenotypic diversity in GSC subpopulations, together suggesting that not all GSCs are equivalent. These observations should be considered when studying GSCs in the laboratory, with implications for the development of treatments that target GSCs and prevent tumor recurrence in patients.

Yeast ribosomal protein L1 is required for the stability of newly synthesized 5S rRNA and the assembly of 60S ribosomal subunits

1993 ◽  
Vol 13 (5) ◽  
pp. 2835-2845
Author(s):  
M Deshmukh ◽  
Y F Tsay ◽  
A G Paulovich ◽  
J L Woolford
Keyword(s):  
Ribosomal Protein ◽  
Ribosomal Subunit ◽  
Single Copy ◽  
5S Rrna ◽  
Gene Encoding ◽  
Ribosomal Subunits ◽  
Ribosomal Protein L1 ◽  
The Stability ◽  
And Function

Ribosomal protein L1 from Saccharomyces cerevisiae binds 5S rRNA and can be released from intact 60S ribosomal subunits as an L1-5S ribonucleoprotein (RNP) particle. To understand the nature of the interaction between L1 and 5S rRNA and to assess the role of L1 in ribosome assembly and function, we cloned the RPL1 gene encoding L1. We have shown that RPL1 is an essential single-copy gene. A conditional null mutant in which the only copy of RPL1 is under control of the repressible GAL1 promoter was constructed. Depletion of L1 causes instability of newly synthesized 5S rRNA in vivo. Cells depleted of L1 no longer assemble 60S ribosomal subunits, indicating that L1 is required for assembly of stable 60S ribosomal subunits but not 40S ribosomal subunits. An L1-5S RNP particle not associated with ribosomal particles was detected by coimmunoprecipitation of L1 and 5S rRNA. This pool of L1-5S RNP remained stable even upon cessation of 60S ribosomal subunit assembly by depletion of another ribosomal protein, L16. Preliminary results suggest that transcription of RPL1 is not autogenously regulated by L1.

scholarly journals Drosophila Glia: Models for Human Neurodevelopmental and Neurodegenerative Disorders

2020 ◽  
Vol 21 (14) ◽  
pp. 4859
Author(s):  
Taejoon Kim ◽  
Bokyeong Song ◽  
Im-Soon Lee
Keyword(s):  
Nervous System ◽  
Neurodegenerative Disorders ◽  
Brain Function ◽  
Cell Biology ◽  
Disease Susceptibility ◽  
Neuronal Development ◽  
In Vivo Model ◽  
Health And Disease ◽  
Drosophila Models

Glial cells are key players in the proper formation and maintenance of the nervous system, thus contributing to neuronal health and disease in humans. However, little is known about the molecular pathways that govern glia–neuron communications in the diseased brain. Drosophila provides a useful in vivo model to explore the conserved molecular details of glial cell biology and their contributions to brain function and disease susceptibility. Herein, we review recent studies that explore glial functions in normal neuronal development, along with Drosophila models that seek to identify the pathological implications of glial defects in the context of various central nervous system disorders.

scholarly journals Effects of osmolytes and macromolecular crowders on stable GAAA tetraloops and their preference for a CG closing base pair

PeerJ ◽  
2018 ◽  
Vol 6 ◽  
pp. e4236
Author(s):  
Kaethe N. Leonard ◽  
Joshua M. Blose
Keyword(s):  
Secondary Structure ◽  
Base Pair ◽  
Structural Changes ◽  
Tertiary Structure ◽  
Vis Spectroscopy ◽  
Rna Tertiary Structure ◽  
The Stability ◽  
And Function ◽  
Peg 8000

Osmolytes and macromolecular crowders have the potential to influence the stability of secondary structure motifs and alter preferences for conserved nucleic acid sequences in vivo. To further understand the cellular function of RNA we observed the effects of a model osmolyte, polyethylene glycol (PEG) 200, and a model macromolecular crowding agent, PEG 8000, on the GAAA tetraloop motif. GAAA tetraloops are conserved, stable tetraloops, and are critical participants in RNA tertiary structure. They also have a thermodynamic preference for a CG closing base pair. The thermal denaturation of model hairpins containing GAAA loops was monitored using UV-Vis spectroscopy in the presence and absence of PEG 200 or PEG 8000. Both of the cosolutes tested influenced the thermodynamic preference for a CG base pair by destabilizing the loop with a CG closing base pair relative to the loop with a GC closing base pair. This result also extended to a related DNA triloop, which provides further evidence that the interactions between the loop and closing base pair are identical for the d(GCA) triloop and the GAAA tetraloop. Our results suggest that in the presence of model PEG molecules, loops with a GC closing base pair may retain some preferential interactions with the cosolutes that are lost in the presence of the CG closing base pair. These results reveal that relatively small structural changes could influence how neutral cosolutes tune the stability and function of secondary structure motifs in vivo.

scholarly journals New Promising Therapeutic Avenues of Curcumin in Brain Diseases

Molecules ◽  
2021 ◽  
Vol 27 (1) ◽  
pp. 236
Author(s):  
Tarek Benameur ◽  
Giulia Giacomucci ◽  
Maria Antonietta Panaro ◽  
Melania Ruggiero ◽  
Teresa Trotta ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Curcuma Longa ◽  
Brain Diseases ◽  
Neuroprotective Effects ◽  
Parkinson’S Diseases ◽  
Brain Structure And Function ◽  
Anti Oxidant ◽  
And Function

Curcumin, the dietary polyphenol isolated from Curcuma longa (turmeric), is commonly used as an herb and spice worldwide. Because of its bio-pharmacological effects curcumin is also called “spice of life”, in fact it is recognized that curcumin possesses important proprieties such as anti-oxidant, anti-inflammatory, anti-microbial, antiproliferative, anti-tumoral, and anti-aging. Neurodegenerative diseases such as Alzheimer’s Diseases, Parkinson’s Diseases, and Multiple Sclerosis are a group of diseases characterized by a progressive loss of brain structure and function due to neuronal death; at present there is no effective treatment to cure these diseases. The protective effect of curcumin against some neurodegenerative diseases has been proven by in vivo and in vitro studies. The current review highlights the latest findings on the neuroprotective effects of curcumin, its bioavailability, its mechanism of action and its possible application for the prevention or treatment of neurodegenerative disorders.

scholarly journals The Amyloid Precursor-like Protein APL-1 Regulates Axon Regeneration

2018 ◽  
Author(s):  
Lewie Zeng ◽  
Rachid El Bejjani ◽  
Marc Hammarlund
Keyword(s):  
Motor Neurons ◽  
Neuronal Development ◽  
Axon Regeneration ◽  
Neuronal Response ◽  
Small Gtpase ◽  
C Elegans ◽  
Protein Levels ◽  
Mature Neurons ◽  
And Function

AbstractMembers of the Amyloid Precursor Protein (APP) family have important functions during neuronal development. However, their physiological functions in the mature nervous system are not fully understood. Here we use the C. elegans GABAergic motor neurons to study the post-developmental function of the APP-like protein APL-1 in vivo. We find that apl-1 has minimum roles in the maintenance of gross neuron morphology and function. However, we show that apl-1 is an inhibitor of axon regeneration, acting on mature neurons to limit regrowth in response to injury. The small GTPase Rab6/RAB-6.2 also inhibits regeneration, and does so in part by maintaining protein levels of APL-1. To inhibit regeneration, APL-1 functions via the E2 domain of its ectodomain; the cytoplasmic tail, transmembrane anchoring, and the E1 domain are not required for this function. Our data defines a novel role for APL-1 in modulating the neuronal response to injury.

scholarly journals Genome-wide sequence identification and expression analysis of N6-methyladenosine demethylase in sugar beet (Beta vulgaris L.) under salt stress

PeerJ ◽  
2022 ◽  
Vol 10 ◽  
pp. e12719
Author(s):  
Jie Cui ◽  
Junli Liu ◽  
Junliang Li ◽  
Dayou Cheng ◽  
Cuihong Dai
Keyword(s):  
Salt Stress ◽  
Sugar Beet ◽  
Profile Analysis ◽  
Rna Modification ◽  
Homologous Proteins ◽  
Genome Wide ◽  
Growth Development ◽  
Gene Structures ◽  
Almost All

In eukaryotes, N6-methyladenosine (m6A) is the most abundant and highly conserved RNA modification. In vivo, m6A demethylase dynamically regulates the m6A level by removing the m6A marker where it plays an important role in plant growth, development and response to abiotic stress. The confirmed m6A demethylases in Arabidopsis thaliana include ALKBH9B and ALKBH10B, both belonging to the ALKB family. In this study, BvALKB family members were identified in sugar beet genome-wide database, and their conserved domains, gene structures, chromosomal locations, phylogeny, conserved motifs and expression of BvALKB genes were analyzed. Almost all BvALKB proteins contained the conserved domain of 2OG-Fe II-Oxy. Phylogenetic analysis suggested that the ten proteins were clustered into five groups, each of which had similar motifs and gene structures. Three Arabidopsis m6A demethylase-homologous proteins (BvALKBH6B, BvALKBH8B and BvALKBH10B) were of particular interest in our study. Expression profile analysis showed that almost all genes were up-regulated or down-regulated to varying degrees under salt stress. More specifically, BvALKBH10B homologous to AtALKBH10B was significantly up-regulated, suggesting that the transcriptional activity of this gene is responsive to salt stress. This study provides a theoretical basis for further screening of m6A demethylase in sugar beet, and also lays a foundation for studying the role of ALKB family proteins in growth, development and response to salinity stress.

scholarly journals In vivo differences between endothelial transcriptional profiles of coronary and iliac arteries revealed by microarray analysis

2008 ◽  
Vol 295 (4) ◽  
pp. H1556-H1561 ◽  
Author(s):  
Ji Zhang ◽  
Kelley A. Burridge ◽  
Morton H. Friedman
Keyword(s):  
Dna Microarrays ◽  
System Development ◽  
Expression Profiles ◽  
Quantitative Polymerase Chain Reaction ◽  
Gene Expression Profiles ◽  
Classical Pathway ◽  
Biological Pathway Analysis ◽  
Almost All ◽  
And Function

Endothelial cells (ECs) from different vascular beds display a remarkable heterogeneity in both structure and function. Phenotypic heterogeneity among arterial ECs is particularly relevant to atherosclerosis since the disease occurs predominantly in major arteries, which vary in their atherosusceptibility. To explore EC heterogeneity between typical atheroprone and atheroresistant arteries, we used DNA microarrays to compare gene expression profiles of freshly harvested porcine coronary (CECs) and iliac artery (IECs) ECs. Statistical analysis revealed 51 genes that were differentially expressed in CECs relative to IECs at a false discovery rate of 5%. Seventeen of these genes are known to be involved in atherogenesis. Consistent with coronary arteries being more atherosusceptible, almost all putative atherogenic genes were overexpressed in CECs, whereas all atheroprotective genes were downregulated, relative to IECs. A subset of the identified genes was validated by quantitative polymerase chain reaction (PCR). PCR results suggest that the differences in expression levels between CECs and IECs for the HOXA10 and HOXA9 genes were >100-fold. Gene ontology (GO) and biological pathway analysis revealed a global expression difference between CECs and IECs. Genes in twelve GO categories, including complement immune activation, immunoglobulin-mediated response, and system development, were significantly upregulated in CECs. CECs also overexpressed genes involved in several inflammatory pathways, including the classical pathway of complement activation and the IGF-1-mediated pathway. The in vivo transcriptional differences between CECs and IECs found in this study may provide new insights into the factors responsible for coronary artery atherosusceptibility.

scholarly journals Role of Choline in Ocular Diseases

2021 ◽  
Vol 22 (9) ◽  
pp. 4733
Author(s):  
Jin-Sun Hwang ◽  
Young-Joo Shin
Keyword(s):  
Parasympathetic Nervous System ◽  
Retinal Hemorrhage ◽  
Ocular Diseases ◽  
Choline Deficiency ◽  
Eye Health ◽  
Development And Differentiation ◽  
Health And Disease ◽  
The Stability ◽  
And Function

Choline is essential for maintaining the structure and function of cells in humans. Choline plays an important role in eye health and disease. It is a precursor of acetylcholine, a neurotransmitter of the parasympathetic nervous system, and it is involved in the production and secretion of tears by the lacrimal glands. It also contributes to the stability of the cells and tears on the ocular surface and is involved in retinal development and differentiation. Choline deficiency is associated with retinal hemorrhage, glaucoma, and dry eye syndrome. Choline supplementation may be effective for treating these diseases.

Sign in / Sign up

Export Citation Format

Share Document