3’UTR Diversity: Expanding Repertoire of RNA Alterations in Human mRNAs

Molecules and Cells, Journal Year: 2023, Volume and Issue: 46(1), P. 48 - 56

Published: Jan. 1, 2023

Genomic information stored in the DNA is transcribed to mRNA and translated proteins.The 3′ untranslated regions (3′UTRs) of serve pivotal roles posttranscriptional gene expression, regulating stability, translation, localization.Similar mutations producing aberrant proteins, RNA alterations expand transcriptome landscape change cellular proteome.Recent global analyses reveal that many genes express various forms altered RNAs, including 3′UTR length variants.Alternative polyadenylation alternative splicing are involved diversifying 3′UTRs, which could act as a hidden layer eukaryotic expression control.In this review, we summarize functions regulations 3′UTRs elaborate on generation functional consequences diversity.Given dynamic control contributes phenotypic complexity, dysregulated diversity might be relevant disease development, cancers.Thus, cancer open exciting new research areas provide avenues for novel theragnostics.

Language: Английский

---

Long 3′UTRs predispose neurons to inflammation by promoting immunostimulatory double-stranded RNA formation

Science Immunology, Journal Year: 2023, Volume and Issue: 8(88)

Published: Oct. 20, 2023

Loss of RNA homeostasis underlies numerous neurodegenerative and neuroinflammatory diseases. However, the molecular mechanisms that trigger neuroinflammation are poorly understood. Viral double-stranded (dsRNA) triggers innate immune responses when sensed by host pattern recognition receptors (PRRs) present in all cell types. Here, we report human neurons intrinsically carry exceptionally high levels immunostimulatory dsRNAs identify long 3'UTRs as giving rise to neuronal dsRNA structures. We found neuron-enriched ELAVL family genes (

Language: Английский

---

Neuronal activity rapidly reprograms dendritic translation via eIF4G2:uORF binding

Nature Neuroscience, Journal Year: 2024, Volume and Issue: 27(5), P. 822 - 835

Published: April 8, 2024

Abstract Learning and memory require activity-induced changes in dendritic translation, but which mRNAs are involved how they regulated unclear. In this study, to monitor depolarization impacts local biology, we employed a dendritically targeted proximity labeling approach followed by crosslinking immunoprecipitation, ribosome profiling mass spectrometry. Depolarization of primary cortical neurons with KCl or the glutamate agonist DHPG caused rapid reprogramming protein expression, where proteins weakly correlated. For subset pre-localized messages, increased translation upstream open reading frames (uORFs) their downstream coding sequences, enabling localized production long-term potentiation, cell signaling energy metabolism. This activity-dependent was accompanied phosphorylation recruitment non-canonical initiation factor eIF4G2, translated uORFs were sufficient confer depolarization-induced, eIF4G2-dependent translational control. These studies uncovered an unanticipated mechanism uORF control eIF4G2 couples activity remodeling.

Language: Английский

---

Variability in SOD1-associated amyotrophic lateral sclerosis: geographic patterns, clinical heterogeneity, molecular alterations, and therapeutic implications

Translational Neurodegeneration, Journal Year: 2024, Volume and Issue: 13(1)

Published: May 29, 2024

Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motor neurons, resulting in global health burden and limited post-diagnosis life expectancy. Although primarily sporadic, familial ALS (fALS) cases suggest genetic basis. This review focuses on SOD1 , the first gene found to be associated with fALS, which has been more recently confirmed genome sequencing. While informative, databases such as ALSoD STRENGTH exhibit regional biases. Through systematic examination mutations from 1993 2023, we different geographic distributions clinical presentations. Even though variants are expressed at protein levels have half-lives dismutase activities, these alterations lead function that not consistently correlated severity. Gain toxic aggregates mutated emerged one key contributors ALS. Therapeutic interventions specifically targeting gain mutant SOD1, including RNA interference antibodies, show promise, but cure remains elusive. provides comprehensive perspective -associated describes molecular features complex landscape highlighting its importance determining diverse manifestations observed patients emphasizing need for personalized therapeutic strategies.

Language: Английский

---

SIRT1 Coordinates Transcriptional Regulation of Neural Activity and Modulates Depression-Like Behaviors in the Nucleus Accumbens

Biological Psychiatry, Journal Year: 2024, Volume and Issue: 96(6), P. 495 - 505

Published: April 3, 2024

Major depression and anxiety disorders are significant causes of disability socioeconomic burden. Despite the prevalence considerable impact these affective disorders, their pathophysiology remains elusive. Thus, there is an urgent need to develop novel therapeutics for conditions. We evaluated role SIRT1 in regulating dysfunctional processes reward by using chronic social defeat stress induce depression- anxiety-like behaviors. Chronic induces physiological behavioral changes that recapitulate depression-like symptomatology alters gene expression programs nucleus accumbens, but cell type-specific this critical structure remain largely unknown.

Language: Английский

---

Choice of Alternative Polyadenylation Sites, Mediated by the RNA-Binding Protein Elavl3, Plays a Role in Differentiation of Inhibitory Neuronal Progenitors

Frontiers in Cellular Neuroscience, Journal Year: 2019, Volume and Issue: 12

Published: Jan. 10, 2019

Alternative polyadenylation (APA) is a widespread mechanism involving about half of the expressed genes, resulting in varying lengths 3'UTR. Variations length and sequence 3'UTR may underlie changes post-transcriptional processing, localization, miRNA targeting stability mRNAs. During embryonic development large array mRNAs exhibit APA, with prevalence longer versions differentiating cells. Little known polyA+ site usage during differentiation mammalian neural progenitors. Here we exploit model adherent stem (ANS) cells, which homogeneously efficiently differentiate into GABAergic neurons. RNAseq data shows global trend towards lengthening 3'UTRs differentiation. Enriched expression variants Pes1 Gng2 was detected mouse brain areas cortical subcortical neuronal differentiation, respectively, by two-probes fluorescent situ hybridization. Among coding genes upregulated ANS cells found Elavl3, neural-specific RNA-binding protein homologous to Drosophila Elav. In insect, Elav regulates choice while interacting paused Pol-II promoters. We tested role Elavl3 silencingElavl3 observed consistent delayed These results indicate that possible additional posttranscriptional RNA modification involved

Language: Английский

---

Application of CRISPR/Cas9 System in the Treatment of Alzheimer’s Disease and Neurodegenerative Diseases

Molecular Neurobiology, Journal Year: 2024, Volume and Issue: 61(11), P. 9416 - 9431

Published: April 19, 2024

Language: Английский

---

MicroRNAs 21 and 199a-3p Regulate Axon Growth Potential through Modulation ofPtenandmTor mRNAs

eNeuro, Journal Year: 2021, Volume and Issue: 8(4), P. ENEURO.0155 - 21.2021

Published: July 1, 2021

Increased mTOR activity has been shown to enhance regeneration of injured axons by increasing neuronal protein synthesis, while PTEN signaling can block attenuate synthesis. MicroRNAs (miRs) have implicated in regulation and expression, previous work spinal cord showed an increase miR-199a-3p after injury (SCI) miR-21 SCI animals that had undergone exercise. Pten mRNA is a target for predicted mTor mRNA. Here, we show are expressed adult dorsal root ganglion (DRG) neurons, used culture preparations test functions the rat miRs DRG embryonic cortical neurons. increases decreases neurons vivo axotomy. In both promotes attenuates neurite growth. directly bound overexpression decreased levels. Conversely, Overexpressing increased overall intra-axonal synthesis cultured DRGs, this The axon growth phenotypes seen with were reversed co-transfecting cDNA expression constructs 3′ untranslated region (UTR) miR sequences deleted. Taken together, these studies indicate injury-induced alterations alter capacity changing through PTEN/mTOR pathway.

Language: Английский

---

MECP2 and the biology of MECP2 duplication syndrome

Journal of Neurochemistry, Journal Year: 2021, Volume and Issue: 159(1), P. 29 - 60

Published: Feb. 27, 2021

MECP2 duplication syndrome (MDS), a rare X-linked genomic disorder affecting predominantly males, is caused by of the chromosomal region containing methyl CpG binding protein-2 (MECP2) gene, which encodes methyl-CpG-binding protein 2 (MECP2), multi-functional required for proper brain development and maintenance function during adulthood. Disease symptoms include severe motor cognitive impairment, delayed or absent speech development, autistic features, seizures, ataxia, recurrent respiratory infections, shortened lifespan. The cellular molecular mechanisms relatively modest increase in causes such disease are poorly understood consequently there no treatments available this fatal disorder. This review summarizes what known to date about structure zcomplex regulation its many functions developing adult brain. Additionally, recent experimental findings on underpinnings MDS based cell culture mouse models reviewed. emerging picture from these studies that neurodegenerative neurons die specific parts central nervous system, including cortex, hippocampus, cerebellum, spinal cord. Neuronal death likely results astrocytic dysfunction, breakdown glutamate homeostatic mechanisms. role elevations expression glial acidic fibrillary (GFAP) astrocytes microtubule-associated protein, Tau, pathogenesis discussed. Lastly, potential therapeutic strategies potentially treat

Language: Английский

---

The Coordination of Local Translation, Membranous Organelle Trafficking, and Synaptic Plasticity in Neurons

Frontiers in Cell and Developmental Biology, Journal Year: 2021, Volume and Issue: 9

Published: July 14, 2021

Neurons are highly complex polarized cells, displaying an extraordinary degree of spatial compartmentalization. At presynaptic and postsynaptic sites, far from the cell body, local protein synthesis is utilized to continually modify synaptic proteome, enabling rapid changes in production support function. Synapses undergo diverse forms plasticity, resulting long-term, persistent synapse strength, which paramount for learning, memory, cognition. It now well-established that translation numerous proteins essential many much work has gone into deciphering strategies neurons use regulate activity-dependent synthesis. Recent studies have pointed a coordination mRNA required plasticity trafficking membranous organelles neurons. This includes co-trafficking RNAs their site action using endosome/lysosome "transports," regulation at synapses, role mitochondria fueling translation. Here, we review our current understanding these mechanisms impact during providing overview novel nuanced regulatory processes involving

Language: Английский

---