Objective: Brown adipose tissue (BAT) plays an important role in mammalian thermogenesis through the expression of uncoupling protein 1 (UCP1). Our previous study identified cytoplasmic polyadenylation element binding protein 2 (CPEB2) as a key regulator that activates the translation of Ucp1 with a long 3'-untranslated region (Ucp1L) in response to adrenergic signaling. Mice lacking CPEB2 or Ucp1L exhibited reduced UCP1 expression and impaired thermogenesis; however, only CPEB2-null mice displayed obesogenic phenotypes.
View Article and Find Full Text PDFExperimental detection of residues critical for protein-protein interactions (PPI) is a time-consuming, costly, and labor-intensive process. Hence, high-throughput PPI-hot spot prediction methods have been developed, but they have been validated using relatively small datasets, which may compromise their predictive reliability. Here, we introduce PPI-hotspot, a novel method for identifying PPI-hot spots using the free protein structure, and validated it on the largest collection of experimentally confirmed PPI-hot spots to date.
View Article and Find Full Text PDFBackground: Local translation at synapses is important for rapidly remodeling the synaptic proteome to sustain long-term plasticity and memory. While the regulatory mechanisms underlying memory-associated local translation have been widely elucidated in the postsynaptic/dendritic region, there is no direct evidence for which RNA-binding protein (RBP) in axons controls target-specific mRNA translation to promote long-term potentiation (LTP) and memory. We previously reported that translation controlled by cytoplasmic polyadenylation element binding protein 2 (CPEB2) is important for postsynaptic plasticity and memory.
View Article and Find Full Text PDFEfficiently delivering exogenous materials into primary neurons and neural stem cells (NSCs) has long been a challenge in neurobiology. Existing methods have struggled with complex protocols, unreliable reproducibility, high immunogenicity, and cytotoxicity, causing a huge conundrum and hindering in-depth analyses. Here, we establish a cutting-edge method for transfecting primary neurons and NSCs, named teleofection, by a two-step process to enhance the formation of biocompatible calcium phosphate (CaP) nanoparticles.
View Article and Find Full Text PDFNeuroinflammation causes neuronal injury in multiple sclerosis (MS) and other neurological diseases. MicroRNAs (miRNAs) are important modulators of neuronal stress responses, but knowledge about their contribution to neuronal protection or damage during inflammation is limited. Here, we constructed a regulatory miRNA-mRNA network of inflamed motor neurons by leveraging cell type-specific miRNA and mRNA sequencing of mice undergoing experimental autoimmune encephalomyelitis (EAE).
View Article and Find Full Text PDFThe late 1990s were banner years in molecular neuroscience; seminal studies demonstrated that local protein synthesis, at or near synapses, was necessary for synaptic plasticity, the underlying cellular basis of learning and memory [1, 2]. The newly made proteins were proposed to "tag" the stimulated synapse, distinguishing it from naive synapses, thereby forming a cellular memory [3]. Subsequent studies demonstrated that the transport of mRNAs from soma to dendrite was linked with translational unmasking at synapses upon synaptic stimulation.
View Article and Find Full Text PDFLong-term maintenance of synaptic connections is important for brain function, which depends on varying proteostatic regulations to govern the functional integrity of neuronal proteomes. Proteostasis supports an interconnection of pathways that regulates the fate of proteins from synthesis to degradation. Defects in proteostatic signaling are associated with age-related functional decline and neurodegenerative diseases.
View Article and Find Full Text PDFOrthomyxo- and bunyaviruses steal the 5' cap portion of host RNAs to prime their own transcription in a process called "cap snatching." We report that RNA modification of the cap portion by host 2'-O-ribose methyltransferase 1 (MTr1) is essential for the initiation of influenza A and B virus replication, but not for other cap-snatching viruses. We identified with in silico compound screening and functional analysis a derivative of a natural product from , called trifluoromethyl-tubercidin (TFMT), that inhibits MTr1 through interaction at its -adenosyl-l-methionine binding pocket to restrict influenza virus replication.
View Article and Find Full Text PDFHepatocellular carcinoma (HCC) is among the most prevalent visceral neoplasms. So far, reliable biomarkers for predicting HCC recurrence in patients undergoing surgery are far from adequate. In the aim of searching for genetic biomarkers involved in HCC development, we performed analyses of cDNA microarrays and found that the DNA repair gene NEIL3 was remarkably overexpressed in tumors.
View Article and Find Full Text PDFEpilepsy is a common neurological disorder, which has been linked to mutations or deletions of RNA binding protein, fox-1 homolog () 3 ()/, a neuronal splicing regulator. However, the mechanism of seizure mediation by RBFOX3 remains unknown. Here, we show that mice with deletion of in gamma-aminobutyric acid (GABA) ergic neurons exhibit spontaneous seizures and high premature mortality due to increased presynaptic release, postsynaptic potential, neuronal excitability, and synaptic transmission in hippocampal dentate gyrus granule cells (DGGCs).
View Article and Find Full Text PDFPolyploidization and polyploidy reversal (depolyploidization) are crucial pathways to conversely alter genomic contents in organisms. Understanding the mechanisms switching between polyploidization and polyploidy reversal should broaden our knowledge of the generation of pathological polyploidy and pave a new path to prevent related diseases.
View Article and Find Full Text PDFStroke is the leading cause of permanent disability and death in the world. The therapy for acute stroke is still limited due to the complex mechanisms underlying stroke-induced neuronal death. The generation of a 17-kDa neurotoxic tau fragment was reported in Alzheimer's disease but it has not been well studied in stroke.
View Article and Find Full Text PDFSusceptibility or resilience to posttraumatic stress disorder (PTSD) depends on one's ability to appropriately adjust synaptic plasticity for coping with the traumatic experience. Activity-regulated mRNA translation synthesizes plasticity-related proteins to support long-term synaptic changes and memory. Hence, cytoplasmic polyadenylation element-binding protein 3-knockout (CPEB3-KO) mice, showing dysregulated translation-associated synaptic rigidity, may be susceptible to PTSD-like behavior.
View Article and Find Full Text PDFBrown adipose tissue (BAT) is a thermogenic organ owing to its unique expression of uncoupling protein 1 (UCP1), which is a proton channel in the inner mitochondrial membrane used to dissipate the proton gradient and uncouple the electron transport chain to generate heat instead of adenosine triphosphate. The discovery of metabolically active BAT in human adults, especially in lean people after cold exposure, has provoked the "thermogenic anti-obesity" idea to battle weight gain. Because BAT can expend energy through UCP1-mediated thermogenesis, the molecular mechanisms regulating UCP1 expression have been extensively investigated at both transcriptional and posttranscriptional levels.
View Article and Find Full Text PDFThe role of protein stabilization in cortical development remains poorly understood. A recessive mutation in the gene is found in a rare neurodevelopmental disorder with intellectual disability, but its pathogenicity and molecular mechanism are unknown. Here, we show that mouse is expressed highly in embryonic cerebral cortex, and deficiency impairs layer 6 neuron production, delays late-born neuronal migration, and disturbs cognition and anxiety behaviors.
View Article and Find Full Text PDFIschemia/reperfusion is a key feature of acute ischemic stroke, which causes neuron dysfunction and death. Exosomes, small extracellular vesicles produced by most cell types, are implicated in the mediation of cellular interactions with their environment. Here, we investigated the contents and functions of exosomes from neurons under ischemic reperfusion injury.
View Article and Find Full Text PDFEukaryotic mRNAs are 5' end capped with a 7-methylguanosine, which is important for processing and translation of mRNAs. Cap methyltransferase 1 (CMTR1) catalyzes 2'-O-ribose methylation of the first transcribed nucleotide (N1 2'-O-Me) to mask mRNAs from innate immune surveillance by retinoic-acid-inducible gene-I (RIG-I). Nevertheless, whether this modification regulates gene expression for neuronal functions remains unexplored.
View Article and Find Full Text PDFAlzheimer's disease (AD) is characterized by a chronic decline in cognitive function and is pathologically typified by cerebral deposition of amyloid-β peptide (Aβ). The production of Aβ is mediated by sequential proteolysis of amyloid precursor protein (APP) by β- and γ-secretases, and has been implicated as the essential determinant of AD pathology. Previous studies have demonstrated that the level of phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] in the membrane may potentially modulate Aβ production.
View Article and Find Full Text PDFOrganogenesis is directed by coordinated cell proliferation and differentiation programs. The hierarchical networks of transcription factors driving mammary gland development and function have been widely studied. However, the contribution of posttranscriptional gene expression reprogramming remains largely unexplored.
View Article and Find Full Text PDFBackground: Alveologenesis is the final stage of lung development to form air-exchanging units between alveoli and blood vessels. Genetic susceptibility or hyperoxic stress to perturb this complicated process can cause abnormal enlargement of alveoli and lead to bronchopulmonary dysplasia (BPD)-associated emphysema. Platelet-derived growth factor receptor α (PDGFRα) signaling is crucial for alveolar myofibroblast (MYF) proliferation and its deficiency is associated with risk of BPD, but posttranscriptional mechanisms regulating PDGFRα synthesis during lung development remain largely unexplored.
View Article and Find Full Text PDFStress alters brain function by modifying the structure and function of neurons and astrocytes. The fine processes of astrocytes are critical for the clearance of neurotransmitters during synaptic transmission. Thus, experience-dependent remodeling of glial processes is anticipated to alter the output of neural circuits.
View Article and Find Full Text PDFFront Behav Neurosci
January 2019
The rodent olfactory bulb (OB) contains two distinct populations of postnatally born interneurons, mainly granule cells (GCs), to support local circuits throughout life. During the early postnatal period (i.e.
View Article and Find Full Text PDFRegulated local translation-whereby specific mRNAs are transported and localized in subcellular domains where they are translated in response to regional signals-allows for remote control of gene expression to concentrate proteins in subcellular compartments. Neurons are highly polarized cells with unique features favoring local control for axonal pathfinding and synaptic plasticity, which are key processes involved in constructing functional circuits in the developing brain. Neurodevelopmental disorders are caused by genetic or environmental factors that disturb the nervous system's development during prenatal and early childhood periods.
View Article and Find Full Text PDFExpression of mitochondrial proton transporter uncoupling protein 1 (UCP1) in brown adipose tissue (BAT) is essential for mammalian thermogenesis. While human UCP1 mRNA exists in a long form only, alternative polyadenylation creates two different isoforms in mice with 10% of UCP1 mRNA found in the long form (Ucp1L) and ~90% in the short form (Ucp1S). We generated a mouse model expressing only Ucp1S and found that it showed impaired thermogenesis due to a 60% drop in UCP1 protein levels, suggesting that Ucp1L is more efficiently translated than Ucp1S.
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