-
Nature Reviews. Molecular Cell Biology Jul 2021Fine-tuning cellular physiology in response to intracellular and environmental cues requires precise temporal and spatial control of gene expression. High-resolution... (Review)
Review
Fine-tuning cellular physiology in response to intracellular and environmental cues requires precise temporal and spatial control of gene expression. High-resolution imaging technologies to detect mRNAs and their translation state have revealed that all living organisms localize mRNAs in subcellular compartments and create translation hotspots, enabling cells to tune gene expression locally. Therefore, mRNA localization is a conserved and integral part of gene expression regulation from prokaryotic to eukaryotic cells. In this Review, we discuss the mechanisms of mRNA transport and local mRNA translation across the kingdoms of life and at organellar, subcellular and multicellular resolution. We also discuss the properties of messenger ribonucleoprotein and higher order RNA granules and how they may influence mRNA transport and local protein synthesis. Finally, we summarize the technological developments that allow us to study mRNA localization and local translation through the simultaneous detection of mRNAs and proteins in single cells, mRNA and nascent protein single-molecule imaging, and bulk RNA and protein detection methods.
Topics: Animals; Cytoplasmic Granules; Gene Expression Regulation; Humans; Protein Biosynthesis; RNA Transport; RNA, Messenger; Ribonucleoproteins
PubMed: 33837370
DOI: 10.1038/s41580-021-00356-8 -
Epilepsy & Behavior Case Reports 2017To investigate the probable ictal origin of unexplained episodic chest pain and if possible to lateralize and localize the epileptic focus.
PURPOSE
To investigate the probable ictal origin of unexplained episodic chest pain and if possible to lateralize and localize the epileptic focus.
METHODS
A 14 year old boy presented with episodic short lasting localized chest pain. His cardiac and other systemic work-up were normal. MRI brain did not reveal any structural pathology. Video telemetry was done for characterization of the paroxysms.
RESULTS
Interictal record showed left fronto-central epileptiform discharges. A left hemispheric, predominantly centroparietal ictal rhythm was identified. The possible localizations of this unusual semiology are somatosensory areas I and II, supplementary sensorimotor area, posterior insula and cingulate cortex. Patient responded remarkably to antiseizure drugs.
CONCLUSION
Pain is a rare manifestation of epilepsy observed in less than 1% of patients. When present, it is usually accompanied by other focal features. This rare occurrence of epileptic seizures masquerading as angina is a novel observation.
PubMed: 28393015
DOI: 10.1016/j.ebcr.2017.02.001 -
American Journal of Neurodegenerative... 2021The prevalence of neurodegenerative diseases is accelerating in rapidly aging global population. Novel and effective diagnostic and therapeutic methods are required to... (Review)
Review
The prevalence of neurodegenerative diseases is accelerating in rapidly aging global population. Novel and effective diagnostic and therapeutic methods are required to tackle the global issue of neurodegeneration in the future. A better understanding of the potential molecular mechanism causing neurodegeneration can shed light on dysfunctional processes in diseased neurons, which can pave the way to design and synthesize novel targets for early diagnosis during the asymptomatic phase of the disease. Abnormal protein aggregation is a hallmark of neurodegenerative diseases which can hamper transportation of cargoes into axons. Recent evidence suggests that disruption of local protein synthesis has been observed in neurodegenerative diseases. Because of their highly asymmetric structure, highly polarized neurons require trafficking of cargoes from the cell body to different subcellular regions to meet the extensive demands of cellular physiology. Localization of mRNAs and subsequent local translation to corresponding proteins in axons is a mechanism which allows neurons to rapidly respond to external stimuli as well as establishing neuronal networks by synthesizing proteins on demand. Axonal protein synthesis is required for axon guidance, synapse formation and plasticity, axon maintenance and regeneration in response to injury. Different types of excitatory and inhibitory neurons in the central and peripheral nervous systems have been shown to localize mRNA. Rising evidence suggests that the repertoire of localizing mRNA in axons can change during aging, indicating a connection between axonal mRNA trafficking and aging diseases such as neurodegeneration. Here, I briefly review the latest findings on the importance of mRNA localization and local translation in neurons and the consequences of their disruption in neurodegenerative diseases. In addition, I discuss recent evidence that dysregulation of mRNA localization and local protein translation can contribute to the formation of neurodegenerative diseases such as Alzheimer's disease, Amyotrophic Lateral Sclerosis, and Spinal Muscular Atrophy. In addition, I discuss recent findings on mRNAs localizing to mitochondria in neurodegeneration.
PubMed: 33815964
DOI: No ID Found -
ENeuro Oct 2023Intracranial electroencephalography (iEEG) provides a unique opportunity to record and stimulate neuronal populations in the human brain. A key step in neuroscience...
Intracranial electroencephalography (iEEG) provides a unique opportunity to record and stimulate neuronal populations in the human brain. A key step in neuroscience inference from iEEG is localizing the electrodes relative to individual subject anatomy and identified regions in brain atlases. We describe a new software tool, Your Advanced Electrode Localizer (YAEL), that provides an integrated solution for every step of the electrode localization process. YAEL is compatible with all common data formats to provide an easy-to-use, drop-in replacement for problematic existing workflows that require users to grapple with multiple programs and interfaces. YAEL's automatic extrapolation and interpolation functions speed localization, especially important in patients with many implanted stereotactic (sEEG) electrode shafts. The graphical user interface is presented in a web browser for broad compatibility and includes an interactive 3D viewer for easier localization of nearby sEEG contacts. After localization is complete, users may enter or import data into YAEL's 3D viewer to create publication-ready visualizations of electrodes and brain anatomy, including identified brain areas from atlases; the response to experimental tasks measured with iEEG; and clinical measures such as epileptiform activity or the results of electrical stimulation mapping. YAEL is free and open source and does not depend on any commercial software. Installation instructions for Mac, Windows, and Linux are available at https://yael.wiki.
Topics: Humans; Electroencephalography; Electrocorticography; Brain; Brain Mapping; Electrodes, Implanted
PubMed: 37857509
DOI: 10.1523/ENEURO.0328-23.2023 -
Frontiers in Integrative Neuroscience 2021Dendrites and axons can extend dozens to hundreds of centimeters away from the cell body so that a single neuron can sense and respond to thousands of stimuli. Thus, for... (Review)
Review
Dendrites and axons can extend dozens to hundreds of centimeters away from the cell body so that a single neuron can sense and respond to thousands of stimuli. Thus, for an accurate function of dendrites and axons the neuronal proteome needs to be asymmetrically distributed within neurons. Protein asymmetry can be achieved by the transport of the protein itself or the transport of the mRNA that is then translated at target sites in neuronal processes. The latter transport mechanism implies local translation of localized mRNAs. The role of local translation in nervous system (NS) development and maintenance is well established, but recently there is growing evidence that this mechanism and its deregulation are also relevant in NS pathologies, including neurodegenerative diseases. For instance, upon pathological signals disease-related proteins can be locally synthesized in dendrites and axons. Locally synthesized proteins can exert their effects at or close to the site of translation, or they can be delivered to distal compartments like the nucleus and induce transcriptional responses that lead to neurodegeneration, nerve regeneration and other cell-wide responses. Relevant key players in the process of local protein synthesis are RNA binding proteins (RBPs), responsible for mRNA transport to neurites. Several neurological and neurodegenerative disorders, including amyotrophic lateral sclerosis or spinal motor atrophy, are characterized by mutations in genes encoding for RBPs and consequently mRNA localization and local translation are impaired. In other diseases changes in the local mRNA repertoire and altered local protein synthesis have been reported. In this review, we will discuss how deregulation of localized translation at different levels can contribute to the development and progression of nervous system pathologies.
PubMed: 34276318
DOI: 10.3389/fnint.2021.689208 -
Science Advances Jul 2022pH controls a large repertoire of chemical and biochemical processes in water. Densely arrayed pH microenvironments would parallelize these processes, enabling their...
pH controls a large repertoire of chemical and biochemical processes in water. Densely arrayed pH microenvironments would parallelize these processes, enabling their high-throughput studies and applications. However, pH localization, let alone its arrayed realization, remains challenging because of fast diffusion of protons in water. Here, we demonstrate arrayed localizations of picoliter-scale aqueous acids, using a 256-electrochemical cell array defined on and operated by a complementary metal oxide semiconductor (CMOS)-integrated circuit. Each cell, comprising a concentric pair of cathode and anode with their current injections controlled with a sub-nanoampere resolution by the CMOS electronics, creates a local pH environment, or a pH "voxel," via confined electrochemistry. The system also monitors the spatiotemporal pH profile across the array in real time for precision pH control. We highlight the utility of this CMOS pH localizer-imager for high-throughput tasks by parallelizing pH-gated molecular state encoding and pH-regulated enzymatic DNA elongation at any selected set of cells.
PubMed: 35895813
DOI: 10.1126/sciadv.abm6815 -
Frontiers in Cell and Developmental... 2021Centrosomes are multifunctional organelles tasked with organizing the microtubule cytoskeleton required for genome stability, intracellular trafficking, and... (Review)
Review
Centrosomes are multifunctional organelles tasked with organizing the microtubule cytoskeleton required for genome stability, intracellular trafficking, and ciliogenesis. Contributing to the diversity of centrosome functions are cell cycle-dependent oscillations in protein localization and post-translational modifications. Less understood is the role of centrosome-localized messenger RNA (mRNA). Since its discovery, the concept of nucleic acids at the centrosome was controversial, and physiological roles for centrosomal mRNAs remained muddled and underexplored. Over the past decades, however, transcripts, RNA-binding proteins, and ribosomes were detected at the centrosome in various organisms and cell types, hinting at a conservation of function. Indeed, recent work defines centrosomes as sites of local protein synthesis, and defined mRNAs were recently implicated in regulating centrosome functions. In this review, we summarize the evidence for the presence of mRNA at the centrosome and the current work that aims to unravel the biological functions of mRNA localized to centrosomes.
PubMed: 34805187
DOI: 10.3389/fcell.2021.782802 -
AIMS Neuroscience 2020The spatial and temporal regulation of gene expression in neurons is an important step in creating functional and structural neuronal networks. The complexity of neurons... (Review)
Review
The spatial and temporal regulation of gene expression in neurons is an important step in creating functional and structural neuronal networks. The complexity of neurons require differential expression of various proteins in different compartments. Highly polarised cells, such as neurons, respond rapidly to different external stimuli by changing their local protein abundance and composition. Neurons can have extensions up to a meter away from their cell body in humans, so it is easy to envisage why they need to manage the synthesis of new proteins locally and on-demand. Recent research has demonstrated that neurons can control the expression of different proteins by localising translationally silent mRNAs, followed by subsequent translation. Neurons use mRNA localization and local translation to achieve different purposes during their life cycle. While developing neurons rely on mRNA localization for axon guidance and synaptogenesis, mature neurons can use mRNA localization for maintenance of essential physiological processes. mRNA localization also plays a role in response to neuron injury to regenerate and restore neuronal connections. Recent microscopic imaging techniques such as live imaging of fluorescently tagged molecules combined with genetic and biochemical studies in neurons have illustrated evolutionarily conserved mechanisms for targeting mRNAs into their correct compartments. This review provides an overview of mRNA localization and local translation in vertebrate and invertebrate neurons and discusses the mechanism by which mRNAs are trafficked into axons. Furthermore, the role of mRNA localization in synaptic activation, as well as axonal injury is explored.
PubMed: 32995487
DOI: 10.3934/Neuroscience.2020016 -
International Journal of Molecular... Aug 2022Matrix metalloproteinases (MMPs) are critical enzymes involved in a variety of cellular processes. MMPs are well known for their ability to degrade the extracellular... (Review)
Review
Matrix metalloproteinases (MMPs) are critical enzymes involved in a variety of cellular processes. MMPs are well known for their ability to degrade the extracellular matrix (ECM) and their extracellular role in cell migration. Recently, more research has been conducted on investigating novel subcellular localizations of MMPs and their intracellular roles at their respective locations. In this review article, we focus on the subcellular localization and novel intracellular roles of two closely related MMPs: membrane-type-1 matrix metalloproteinase (MT1-MMP) and matrix metalloproteinase-2 (MMP-2). Although MT1-MMP is commonly known to localize on the cell surface, the protease also localizes to the cytoplasm, caveolae, Golgi, cytoskeleton, centrosome, and nucleus. At these subcellular locations, MT1-MMP functions in cell migration, macrophage metabolism, invadopodia development, spindle formation and gene expression, respectively. Similar to MT1-MMP, MMP-2 localizes to the caveolae, mitochondria, cytoskeleton, nucleus and nucleolus and functions in calcium regulation, contractile dysfunction, gene expression and ribosomal RNA transcription. Our particular interest lies in the roles MMP-2 and MT1-MMP serve within the nucleus, as they may provide critical insights into cancer epigenetics and tumor migration and invasion. We suggest that targeting nuclear MT1-MMP or MMP-2 to reduce or halt cell proliferation and migration may lead to the development of new therapies for cancer and other diseases.
Topics: Extracellular Matrix; Humans; Matrix Metalloproteinase 14; Matrix Metalloproteinase 2; Matrix Metalloproteinases; Metalloendopeptidases; Neoplasms
PubMed: 36076910
DOI: 10.3390/ijms23179513 -
Nuclear Medicine and Biology 2021In oncology, the holy grail of radiotherapy is specific radiation dose deposition in tumours with minimal healthy tissue toxicity. If used appropriately, injectable,... (Review)
Review
In oncology, the holy grail of radiotherapy is specific radiation dose deposition in tumours with minimal healthy tissue toxicity. If used appropriately, injectable, systemic radionuclide therapies could meet these criteria, even for treatment of micrometastases and single circulating tumour cells. The clinical use of α and β particle-emitting molecular radionuclide therapies is rising, however clinical translation of Auger electron-emitting radionuclides is hampered by uncertainty around their exact subcellular localisation, which in turn affects the accuracy of dosimetry. This review aims to discuss and compare the advantages and disadvantages of various subcellular localisation methods available to localise radiopharmaceuticals and radionuclides for in vitro investigations.
Topics: Alpha Particles; Radiation Dosage; Radiopharmaceuticals
PubMed: 33964707
DOI: 10.1016/j.nucmedbio.2021.03.010