scholarly journals Ribosome traffic jam in neurodegeneration: decoding hurdles in Huntington disease

Cell Stress ◽  
2021 ◽  
Vol 5 (6) ◽  
pp. 86-88
Author(s):  
Srinivasa Subramaniam
Keyword(s):  
Protein Synthesis ◽  
Huntington Disease ◽  
Molecular Mechanisms ◽  
Mrna Translation ◽  
Brain Disorders ◽  
Mrna Transcript ◽  
Traffic Jam ◽  
Ribosome Stalling ◽  
Mrna Transcripts ◽  
Short Commentary

A ribosome typically moves at a particular rate on a given mRNA transcript to decode the nucleic acid information required to synthesize proteins. The speed and directionality of the ribosome movements during mRNA translation are determined by the mRNA sequence and structure and by various decoding factors. However, the molecular mechanisms of this remarkable movement during protein synthesis, or its relevance in brain disorders, remain unknown. Recent studies have indicated that defects in protein synthesis occur in various neurodegenerative diseases, but the mechanistic details are unclear. This is a major problem because identifying the factors that determine protein synthesis defects may offer new avenues for developing therapeutic remedies for currently incurable diseases like neurodegenerative disorders. Based on our recent study (Eshraghi et al., Nat Commun 12(1):1461; doi: 10.1038/s41467-021-21637-y), this short commentary will review the mechanistic understanding of Huntingtin (HTT)-mediated ribosome stalling indicating that central defects in protein synthesis in Huntington disease (HD) are orchestrated by jamming of ribosomes on mRNA transcripts.

scholarly journals Ionizing Radiation and Translation Control: A Link to Radiation Hormesis?

2020 ◽  
Vol 21 (18) ◽  
pp. 6650
Author(s):  
Usha Kabilan ◽  
Tyson E. Graber ◽  
Tommy Alain ◽  
Dmitry Klokov
Keyword(s):  
Protein Synthesis ◽  
Ionizing Radiation ◽  
Molecular Mechanisms ◽  
Low Dose ◽  
Mrna Translation ◽  
Cellular Responses ◽  
Translation Control ◽  
Cis Acting ◽  
Radiation Hormesis ◽  
Downstream Signaling

Protein synthesis, or mRNA translation, is one of the most energy-consuming functions in cells. Translation of mRNA into proteins is thus highly regulated by and integrated with upstream and downstream signaling pathways, dependent on various transacting proteins and cis-acting elements within the substrate mRNAs. Under conditions of stress, such as exposure to ionizing radiation, regulatory mechanisms reprogram protein synthesis to translate mRNAs encoding proteins that ensure proper cellular responses. Interestingly, beneficial responses to low-dose radiation exposure, known as radiation hormesis, have been described in several models, but the molecular mechanisms behind this phenomenon are largely unknown. In this review, we explore how differences in cellular responses to high- vs. low-dose ionizing radiation are realized through the modulation of molecular pathways with a particular emphasis on the regulation of mRNA translation control.

scholarly journals Ribosome Profiling Reveals a Dichotomy Between Ribosome Occupancy of Nuclear-Encoded and Mitochondrial-Encoded OXPHOS mRNA Transcripts in a Striatal Cell Model of Huntington Disease

2021 ◽  
Author(s):  
S Subramaniam ◽  
N Shahani
Keyword(s):  
Huntington Disease ◽  
High Throughput Sequencing ◽  
Cell Model ◽  
Mrna Translation ◽  
Ribosome Profiling ◽  
Mitochondrial Functions ◽  
Mrna Transcripts ◽  
Mild Reduction ◽  
Mitochondrial Transcripts ◽  
Command Signals

AbstractHuntington disease (HD) is caused by an expanded polyglutamine mutation in huntingtin (mHTT), which promotes a prominent atrophy in the striatum and subsequent psychiatric, cognitive, and choreiform movements. Multiple lines of evidence point to an association between HD and aberrant striatal mitochondrial functions. However, present knowledge about whether (or how) mitochondrial mRNA translation is differentially regulated in HD remains unclear. We have recently applied ribosome profiling (Ribo-Seq), a technique based on the high-throughput sequencing of ribosome-protected mRNA fragments, to analyze detailed snapshots of ribosome occupancy of the mitochondrial mRNA transcripts in control and HD striatal cells. Ribo-seq data revealed almost unaltered ribosome occupancy on the nuclear-encoded mitochondrial transcripts involved in oxidative phosphorylation (OXPHOS) and only a mild reduction in ribosome occupancy on a few selected transcripts (SHDA, Ndufv1, Timm23, Tomm5, and Mrps22) in HD cells. By contrast, ribosome occupancy of mitochondrially encoded OXPHOS mRNAs (mtNd-1, mtNd-2, mtNd-4, mtNd-4l, mtNd-5, mtNd-6, mt-Co1, mtCyt b, and mt-ATP8) was dramatically increased, implying widespread dichotomous effects on ribosome occupancy and OXPHOS mRNA translation in HD. Thus, mHTT may command signals that specifically regulate translation of the mitochondrial OXPHOS transcripts and influence HD pathogenesis.

scholarly journals TOP mRNPs: Molecular Mechanisms and Principles of Regulation

Biomolecules ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. 969 ◽  
Author(s):  
Eric Cockman ◽  
Paul Anderson ◽  
Pavel Ivanov
Keyword(s):  
Protein Synthesis ◽  
Translational Control ◽  
Gene Networks ◽  
Cellular Response ◽  
Ribosome Biogenesis ◽  
Molecular Mechanisms ◽  
Mrna Translation ◽  
Ribonucleoprotein Complexes ◽  
Global Protein Synthesis ◽  
Protein Components

The cellular response to changes in the surrounding environment and to stress requires the coregulation of gene networks aiming to conserve energy and resources. This is often achieved by downregulating protein synthesis. The 5’ Terminal OligoPyrimidine (5’ TOP) motif-containing mRNAs, which encode proteins that are essential for protein synthesis, are the primary targets of translational control under stress. The TOP motif is a cis-regulatory RNA element that begins directly after the m7G cap structure and contains the hallmark invariant 5’-cytidine followed by an uninterrupted tract of 4–15 pyrimidines. Regulation of translation via the TOP motif coordinates global protein synthesis with simultaneous co-expression of the protein components required for ribosome biogenesis. In this review, we discuss architecture of TOP mRNA-containing ribonucleoprotein complexes, the principles of their assembly, and the modes of regulation of TOP mRNA translation.

Mechanism of miRNA-mediated repression of mRNA translation

2013 ◽  
Vol 54 ◽  
pp. 29-38 ◽  
Author(s):  
Tamas Dalmay
Keyword(s):  
Mrna Translation ◽  
Translational Repression ◽  
Mrna Transcript ◽  
Subtle Difference ◽  
Protein Coding ◽  
Complementary Sequences ◽  
Mrna Transcripts ◽  
Sequence Complementarity ◽  
Recent Developments ◽  
Two Kingdoms

MicroRNAs regulate the expression of protein-coding genes in animals and plants. They function by binding to mRNA transcripts with complementary sequences and inhibit their expression. The level of sequence complementarity between the microRNA and mRNA transcript varies between animal and plant systems. Owing to this subtle difference, it was initially believed that animal and plant microRNAs act in different ways. Recent developments revealed that, although differences still remain in the two kingdoms, the differences are smaller than first thought. It is now clear that both animal and plant microRNAs mediate both translational repression of intact mRNAs and also cause mRNA degradation.

scholarly journals Translational Mechanisms that Govern Milk Protein Levels and Composition

2004 ◽  
Author(s):  
Itamar Barash ◽  
Robert E. Rhoads
Keyword(s):  
Amino Acids ◽  
Protein Synthesis ◽  
Mammary Gland ◽  
Total Protein ◽  
Milk Protein ◽  
Molecular Mechanisms ◽  
Mrna Translation ◽  
Cytoplasmic Polyadenylation ◽  
Translational Initiation ◽  
Lactogenic Hormones

Original objectives: The long term objective of the project is to achieve higher content of protein in the milk of ruminants by modulating the translational machinery in the mammary gland. The first specific aim of the BARD proposal was to characterize responsiveness of various experimental systems to combination of lactogenic hormones and amino acids with particular emphasis on discrimination between the control of total protein synthesis and milk protein synthesis. Based on the results, we planned to proceed by characterizing the stage of protein synthesis in which the stimulation by lactogenic hormones and amino acid occur and finally we proposed to identify which components of the translation machinery are modified. Background to the topic: Milk protein is the most valuable component in milk, both for direct human consumption and for manufacturing cheese and other protein-based products. Attempts to augment protein content by the traditional methods of genetic selection and improved nutritional regimes have failed. The proposal was based on recent results suggesting that the limiting factor for augmenting protein synthesis in the bovine mammary gland is the efficiency of converting amino acids to milk proteins. Major conclusions, solutions, achievements: Insulin and prolactin synergistically stimulate â-casein mRNA translation by cytoplasmatic polyadenylation. The interaction between insulin and prolactin was demonstrated two decades ago as crucial for milk-protein synthesis, but the molecular mechanisms involved were not elucidated. We found in differentiated CID 9 mouse mammary epithelial cells line that insulin and prolactin synergistically increases the rate of milk protein mRNA translation. We focused on â-casein, the major milk protein, and found that the increase in â-casein mRNA translation was reflected in a shift to larger polysomes, indicating an effect on translational initiation. Inhibitors of the PI3K, mTOR, and MAPK pathways blocked insulin-stimulated total protein and â-casein synthesis but not the synergistic stimulation. Conversely, cordycepin, a polyadenylation inhibitor, abolished synergistic stimulation of protein synthesis without affecting insulin-stimulated translation. The poly(A) tract of â-casein mRNA progressively increased over 30 min of treatment with insulin plus prolactin. The 3’-untranslated region of â-casein mRNA was found to contain a cytoplasmic polyadenylation element (CPE), and in reporter constructs, this was sufficient for the translational enhancement and mRNA-specific polyadenylation. Furthermore, insulin and prolactin stimulated phosphorylation of cytoplasmic polyadenylation element binding protein (CPEB) but did not increase cytoplasmic polyadenylation. 

scholarly journals Functional Characterization of the m6A-Dependent Translational Modulator PfYTH.2 in the Human Malaria Parasite

mBio ◽  
2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Ameya Sinha ◽  
Sebastian Baumgarten ◽  
Amy Distiller ◽  
Emma McHugh ◽  
Patty Chen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Plasmodium Falciparum ◽  
Protein Synthesis ◽  
Malaria Parasite ◽  
Binding Proteins ◽  
Functional Characterization ◽  
Mrna Translation ◽  
Content Type ◽  
Mrna Transcripts

ABSTRACT Posttranscriptional regulation of gene expression is central to the development and replication of the malaria parasite, Plasmodium falciparum, within its human host. The timely coordination of RNA maturation, homeostasis, and protein synthesis relies on the recruitment of specific RNA-binding proteins to their cognate target mRNAs. One possible mediator of such mRNA-protein interactions is the N6-methylation of adenosines (m6A), a prevalent mRNA modification of parasite mRNA transcripts. Here, we used RNA protein pulldowns, RNA modification mass spectrometry, and quantitative proteomics to identify two P. falciparum YTH domain proteins (PfYTH.1 and PfYTH.2) as m6A-binding proteins during parasite blood-stage development. Interaction proteomics revealed that PfYTH.2 associates with the translation machinery, including multiple subunits of the eukaryotic initiation factor 3 (eIF3) and poly(A)-binding proteins. Furthermore, knock sideways of PfYTH.2 coupled with ribosome profiling showed that this m6A reader is essential for parasite survival and is a repressor of mRNA translation. Together, these data reveal an important missing link in the m6A-mediated mechanism controlling mRNA translation in a unicellular eukaryotic pathogen. IMPORTANCE Infection with the unicellular eukaryotic pathogen Plasmodium falciparum causes malaria, a mosquito-borne disease affecting more than 200 million and killing 400,000 people each year. Underlying the asexual replication within human red blood cells is a tight regulatory network of gene expression and protein synthesis. A widespread mechanism of posttranscriptional gene regulation is the chemical modification of adenosines (m6A), through which the fate of individual mRNA transcripts can be changed. Here, we report on the protein machinery that “reads” this modification and “translates” it into a functional outcome. We provide mechanistic insight into one m6A reader protein and show that it interacts with the translational machinery and acts as a repressor of mRNA translation. This m6A-mediated phenotype has not been described in other eukaryotes as yet, and the functional characterization of the m6A interactome will ultimately open new avenues to combat the disease.

scholarly journals Mutant Huntingtin stalls ribosomes and represses protein synthesis in a cellular model of Huntington disease

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Mehdi Eshraghi ◽  
Pabalu P. Karunadharma ◽  
Juliana Blin ◽  
Neelam Shahani ◽  
Emiliano P. Ricci ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Huntington Disease ◽  
Ribosomal Proteins ◽  
Mutant Huntingtin ◽  
Translation Elongation ◽  
Polyglutamine Expansion ◽  
Ribosome Stalling ◽  
Mrna Targets ◽  
Discernible Effect

AbstractThe polyglutamine expansion of huntingtin (mHTT) causes Huntington disease (HD) and neurodegeneration, but the mechanisms remain unclear. Here, we found that mHtt promotes ribosome stalling and suppresses protein synthesis in mouse HD striatal neuronal cells. Depletion of mHtt enhances protein synthesis and increases the speed of ribosomal translocation, while mHtt directly inhibits protein synthesis in vitro. Fmrp, a known regulator of ribosome stalling, is upregulated in HD, but its depletion has no discernible effect on protein synthesis or ribosome stalling in HD cells. We found interactions of ribosomal proteins and translating ribosomes with mHtt. High-resolution global ribosome footprint profiling (Ribo-Seq) and mRNA-Seq indicates a widespread shift in ribosome occupancy toward the 5′ and 3′ end and unique single-codon pauses on selected mRNA targets in HD cells, compared to controls. Thus, mHtt impedes ribosomal translocation during translation elongation, a mechanistic defect that can be exploited for HD therapeutics.

scholarly journals Mitochondrial Defects in the Respiratory Complex I Contribute to Impaired Translational Initiation via ROS and Energy Homeostasis in SMA Motor Neurons

2020 ◽  
Author(s):  
Maximilian Paul Thelen ◽  
Brunhilde Wirth ◽  
Min Jeong Kye
Keyword(s):  
Protein Synthesis ◽  
Motor Neurons ◽  
Energy Homeostasis ◽  
Molecular Mechanisms ◽  
Muscular Atrophy ◽  
Mrna Translation ◽  
High Energy ◽  
Translational Initiation ◽  
Atp Production ◽  
Smn Protein

Abstract BackgroundSpinal muscular atrophy (SMA) is a neuromuscular disease, characterized by loss of lower alpha motor neurons, which leads to proximal muscle weakness. SMA is caused by reduced levels of Survival of Motor Neuron (SMN) due to biallelic deletions or mutations in the SMN1 gene and mainly non-functional SMN2 copy gene. When SMN levels fall under a certain threshold, a plethora of cellular pathways are disturbed including RNA processing, protein synthesis, metabolic defects and dysfunctional mitochondria. Dysfunctional mitochondria can harm cells by decreased ATP production, but also by increased oxidative stress due to elevated production of reactive oxygen species (ROS). Since neurons mainly produce energy via mitochondrial oxidative phosphorylation to cover their high energy demands, restoring metabolic/ oxidative homeostasis can be beneficial in SMA pathology.MethodsWe performed whole proteome analysis of murine primary motor neurons using mass spectrometry to identify molecular mechanisms altered by SMN deficiency, which contribute to SMA pathology. Identified pathways were independently confirmed by biochemical and molecular biological methods as well as imaging analysis. Furthermore, cellular energy and ROS levels were biochemically measured in WT and SMA motor neurons.ResultsWe report that primary SMA motor neurons show disturbed energy homeostasis such as a reduced number of functional mitochondria, impaired glucose uptake and overall lower basal ATP concentrations. In addition, elevated ROS levels cause an increase of protein carbonylation and impaired protein synthesis efficiency in SMA motor neurons. Counteracting these cellular impairments with supplemented pyruvate reduced elevated ROS levels, increased ATP and SMN protein levels in SMA motor neurons. Furthermore, we found that pyruvate-mediated SMN protein synthesis is mTOR-dependent. Most importantly, we show that ROS regulates global protein synthesis at the translational initiation step, which is impaired in SMA.ConclusionIn summary, we found that excessive amount of cellular ROS caused by defective mitochondria inhibits initiation of mRNA translation, which results in pathological phenotypes often observed in degenerative neurons. As many neuropathies share patho-phenotypes such as dysfunctional mitochondria, excessive ROS and impaired protein synthesis.Our findings suggest a new molecular networking system among these pathways.

scholarly journals Plants Utilise Ancient Conserved Peptide Upstream Open Reading Frames as Environmental Sensors

2021 ◽  
Author(s):  
Barry Causier ◽  
Tayah Hopes ◽  
Mary McKay ◽  
Zachary Paling ◽  
Brendan Davies
Keyword(s):  
Protein Synthesis ◽  
Growth And Development ◽  
Open Reading Frames ◽  
Environmental Sensors ◽  
Environmental Signals ◽  
Broad Application ◽  
Ribosome Stalling ◽  
Mrna Transcripts ◽  
Upstream Open Reading Frames ◽  
Reading Frames

The regulation of protein synthesis plays an important role in growth and development in all organisms. Upstream open reading frames (uORFs) are commonly found in eukaryotic mRNA transcripts and typically attenuate the translation of associated downstream main ORFs (mORFs). Conserved peptide uORFs (CPuORFs) are a rare subset of uORFs, some of which have been shown to conditionally regulate translation by ribosome stalling. Here we identify three Arabidopsis CPuORFs of ancient origin that regulate translation of any downstream ORF, in response to agriculturally significant environmental signals: heat stress and water limitation. We provide evidence that different sequence classes of CPuORF stall ribosomes during different phases of translation and show that plant CPuORFs act as environmental sensors that can be utilised as inducible regulators of translation with broad application.

High Altitude hypoxia

2020 ◽  
Vol 17 ◽  
Author(s):  
Asma Babar ◽  
Kifayatullah Mengal ◽  
Abdul Hanan Babar ◽  
Shixin Wu ◽  
Mujahid Ali Shah ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
High Altitude ◽  
Molecular Mechanisms ◽  
Strong Association ◽  
Haemoglobin Concentration ◽  
Metabolic Reprogramming ◽  
Molecular Networks ◽  
Whole Genome ◽  
Gene Expressions ◽  
Transcriptional Responses

: The world highest and largest altitude area is called the Qinghai-Tibetan plateau (QTB), which harbors unique animal and plant species. Mammals that inhabit the higher altitude regions have adapted well to the hypoxic conditions. One of the main stressors at high altitude is hypoxia. Metabolic responses to hypoxia play important roles in cell survival strategies and some diseases. However, the homeostatic alterations that equilibrate variations in the demand and supply of energy to maintain organismal function in a prolonged low O2 environment persist partly understood, making it problematic to differentiate adaptive from maladaptive responses in hypoxia. Tibetans and yaks are two perfect examples innate to the plateau for high altitude adaptation. By the scan of the whole-genome, EPAS1 and EGLN1 were identified as key genes associated with sustained haemoglobin concentration in high altitude mammals for adaptation. The yak is a much more ancient mammal which has existed on QTB longer than humans, it is, therefore, possible that natural selection represented a diverse group of genes/pathways in yaks. Physiological characteristics are extremely informative in revealing molecular networks associated with inherited adaptation, in addition to the whole-genome adaptive changes at the DNA sequence level. Gene-expression can be changed by a variety of signals originating from the environment, and hypoxia is the main factor amongst them. The hypoxia-inducible factors (HIF-1α and EPAS1/HIF-2α) are the main regulators of oxygen in homeostasis which play a role as maestro regulators of adaptation in hypoxic reaction of molecular mechanisms. (Vague) The basis of this review is to present recent information regarding the molecular mechanism involved in hypoxia that regulates candidate genes and proteins. Many transcriptional responses toward hypoxia are facilitated by HIFs that change the number of gene expressions and help in angiogenesis, erythropoiesis, metabolic reprogramming and metastasis. HIFs also activate several signals highlighting a strong association between hypoxia, the misfolded proteins’ accumulation in the endoplasmic reticulum in stress and activation of unfolded protein response (UPR). It was observed that at high-altitude, pregnancies yield a low birth weight ∼100 g per1000 m of the climb. (Vague) It may involve variation in the events of energy-demanding, like protein synthesis. Prolonged hypobaric hypoxia causes placental ER stress, which in turn, moderates protein synthesis and reduces proliferation. Further, Cardiac hypertrophy by cytosolic Ca2+ raises and Ca2+/calmodulin, calcineurin stimulation, NF-AT3 pathway might be caused by an imbalance in Sarcoplasmic reticulum ER Ca2, might be adaptive in beginning but severe later.

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