DOCSLIB.ORG

SINEUP Non-Coding Rnas Rescue Defective Frataxin Expression and Activity in a Cellular Model of Friedreich’S Ataxia

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
SINEUP Non-Coding Rnas Rescue Defective Frataxin Expression and Activity in a Cellular Model of Friedreich’S Ataxia International School of Advanced Studies Area of Neuroscience Curriculum in Functional and Structural Genomics SINEUP non-coding RNAs rescue defective frataxin expression and activity in a cellular model of Friedreich’s Ataxia Thesis submitted for the degree of “Doctor Philosophiae” CANDIDATE SUPERVISOR Carlotta Bon Prof. Stefano Gustincich 12th October 2018 DECLARATION The work described in this thesis was carried out at SISSA (International School of Advanced Studies) in Trieste, between November 2014 and September 2018 with the exception of functional experiment on FRDA-derived lymphoblasts stably expressing miniSINEUPs, which were performed at the Department of Biomedicine and Prevention, Laboratory of Signal Transduction, University of Rome Tor Vergata, Rome, Italy, under the supervision of Ivano Condò, PhD. This work was supported by Telethon Grant GGP15004 to Professor Stefano Gustincich, Ivano Condò and Professor Antonello Mallamaci and by the Italian Ministry of Education, University and Research (FIRB grant prot. RBAP11FRE9) to Professor Stefano Gustincich. Part of the work described in this thesis is included in the following papers: Structural determinants of the SINE B2 element embedded in the long non- coding RNA activator of translation AS Uchl1. Peter Podbevšek, Francesca Fasolo, Carlotta Bon, Laura Cimatti, Sabine Reißer, Piero Carninci, Giovanni Bussi, Silvia Zucchelli1, Janez Plavec*, and Stefano Gustincich*. Scientific Reportsvolume 8, Article number: 3189 (2018). doi: https://doi.org/10.1038/s41598-017-14908-6 SINEUP non-coding RNAs rescue defective frataxin expression and activity in a cellular model of Friedreich’s Ataxia. Bon C, Luffarelli R, Russo R, Fortuni S, Santulli C, Fimiani C, Persichetti F, Cotella D, Mallamaci A, Santoro C, Carninci P, Testi R, Zucchelli S, Condò I* and Gustincich S*. Manuscript submitted. TABLE OF CONTENTS ABSTRACT ............................................................................................................................. I ACRONYMS ........................................................................................................................ III INTRODUCTION .................................................................................................................. 1 RNA THERAPEUTICS: THE PRESENT STATE .......................................................................... 1 Inhibitory RNAs ................................................................................................................ 2 AntiSense Oligonucleotides (ASOs) .......................................................................................................... 2 RNA interference (RNAi) .......................................................................................................................... 4 Anti-miRNA oligonucleotides (AntagoMIR) ............................................................................................ 6 Activatory RNAs ............................................................................................................... 7 Non-degradative ASOs .............................................................................................................................. 7 RNA activation (RNAa) ............................................................................................................................ 7 NMHV transcription factors ...................................................................................................................... 8 SINEUPS: A NEW FUNCTIONAL CLASS OF ANTISENSE LNCRNAS ........................................ 9 AS Uchl1 ......................................................................................................................... 12 Natural SINEUPs ........................................................................................................... 13 invSINEB2: structure and function .......................................................................................................... 14 Synthetic SINEUPs ......................................................................................................... 16 miniSINEUPs ................................................................................................................. 18 SINEUPs as a new platform for increasing gene expression ........................................ 19 FRIEDREICH’S ATAXIA ........................................................................................................ 21 Clinical features ............................................................................................................. 21 Genetic basis of the disease ........................................................................................... 23 FXN gene ................................................................................................................................................. 23 GAA triplet repeat expansion .................................................................................................................. 24 FXN transcription inhibition .......................................................................................... 26 Epigenetic changes associated with FRDA ............................................................................................. 28 Frataxin .......................................................................................................................... 29 Structure ................................................................................................................................................... 29 Processing ................................................................................................................................................ 30 The mystery of frataxin cellular function ................................................................................................ 31 Therapeutical approaches in FRDA: goals and objectives ........................................... 33 MATERIAL AND METHODS ........................................................................................... 37 RESULTS .............................................................................................................................. 43 1. SYNTHETIC SINEUP-FXN: DESIGN AND SCREENING ................................................ 43 2. SYNTHETIC MINISINEUP-FXN ARE ACTIVE IN VITRO ............................................... 48 3. PROTEIN RESCUE IN FRDA-DERIVED FIBROBLASTS .................................................. 50 4. THERAPEUTICAL PROTEIN RESCUE IN FRDA-DERIVED LYMPHOBLASTS .................. 52 5. FUNCTIONAL RESCUE OF DISEASE-ASSOCIATED PHENOTYPE .................................... 54 DISCUSSION ........................................................................................................................ 56 CONFERENCE PROCEEDINGS ...................................................................................... 60 LIST OF PUBBLICATIONS ............................................................................................... 61 SUPPLEMENTARY FIRGURES & TABLES .................................................................. 62 SUPPLEMENTARY FIGURE S1 .............................................................................................. 62 SUPPLEMENTARY FIGURE S2 .............................................................................................. 63 SUPPLEMENTARY FIGURE S3 .............................................................................................. 65 ACKNOWLEDGMENTS .................................................................................................... 66 BIBLIOGRAPHY ................................................................................................................. 67 ABSTRACT During the last decade RNA-based therapy had a burst of interest due to all undeniable advantages such as high selectivity, low off-target toxicity, and the potential scalability to a large repertory of untreatable human diseases. Most RNA therapeutic molecules are inhibitory RNAs and have been developed to down-regulate expression of pathogenic genes. Nevertheless, a large group of diseases would strongly benefit from the discovery of RNAs able to increase gene expression and restore physiological transcription and/or translation of a specific target when low expression is pathogenic. Recently, gene-specific transcriptional activating RNAs (RNAa) (1) and non- degradative antisense oligonucleotide (ASOs) (2) have been largely employed to increase the expression of selected genes. On the other hand, despite its great potential, long non-coding translational activation as therapeutic tool is still at its infancy. We have previously described SINEUPs, natural and synthetic antisense long non-coding RNAs, which promote translation of partially overlapping mRNAs through the activity of an embedded SINEB2 domain. In this study, we focused the attention on the SINEUP-mediated up-regulation as a possible treatment to rescue haploinsufficient gene-dosage. In this context, we developed SINEUPs for Friedreich’s ataxia (FRDA), a life- threatening disease with neuro- and cardio-degenerative progression (3) representing the most frequent type of inherited ataxia, and affecting more than 15,000 patients in Western countries (4). This monogenic disease is caused by the hyperexpansion of naturally occurring GAA repeats in the first intron of the frataxin (FXN) gene, encoding for frataxin, a protein implicated in the biogenesis
Load more

Recommended publications
  • Whole Genome and Segmental Duplications Underlie Glutamine Synthetase and Phosphoenolpyruvate Carboxylase Diversity in Narrow-Leafed Lupin (Lupinus Angustifolius L.)
    International Journal of Molecular Sciences Article A Tale of Two Families: Whole Genome and Segmental Duplications Underlie Glutamine Synthetase and Phosphoenolpyruvate Carboxylase Diversity in Narrow-Leafed Lupin (Lupinus angustifolius L.) Katarzyna B. Czy˙z 1,* , Michał Ksi ˛a˙zkiewicz 2 , Grzegorz Koczyk 1 , Anna Szczepaniak 2, Jan Podkowi ´nski 3 and Barbara Naganowska 2 1 Department of Biometry and Bioinformatics, Institute of Plant Genetics, Polish Academy of Sciences, 60-479 Poznan, Poland; [email protected] 2 Department of Genomics, Institute of Plant Genetics, Polish Academy of Sciences, 60-479 Poznan, Poland; [email protected] (M.K.); [email protected] (B.N.) 3 Department of Genomics, Institute of Bioorganic Chemistry, Polish Academy of Sciences, 61-704 Poznan, Poland * Correspondence: [email protected] Received: 17 February 2020; Accepted: 6 April 2020; Published: 8 April 2020 Abstract: Narrow-leafed lupin (Lupinus angustifolius L.) has recently been supplied with advanced genomic resources and, as such, has become a well-known model for molecular evolutionary studies within the legume family—a group of plants able to fix nitrogen from the atmosphere. The phylogenetic position of lupins in Papilionoideae and their evolutionary distance to other higher plants facilitates the use of this model species to improve our knowledge on genes involved in nitrogen assimilation and primary metabolism, providing novel contributions to our understanding of the evolutionary history of legumes. In this study, we present a complex characterization of two narrow-leafed lupin gene families—glutamine synthetase (GS) and phosphoenolpyruvate carboxylase (PEPC). We combine a comparative analysis of gene structures and a synteny-based approach with phylogenetic reconstruction and reconciliation of the gene family and species history in order to examine events underlying the extant diversity of both families.
    [Show full text]
  • ARTICLES Functional Mitochondrial Heterogeneity in Heteroplasmic
    0031-3998/00/4802-0143 PEDIATRIC RESEARCH Vol. 48, No. 2, 2000 Copyright © 2000 International Pediatric Research Foundation, Inc. Printed in U.S.A. ARTICLES Functional Mitochondrial Heterogeneity in Heteroplasmic Cells Carrying the Mitochondrial DNA Mutation Associated with the MELAS Syndrome (Mitochondrial Encephalopathy, Lactic Acidosis, and Strokelike Episodes) ANNETTE BAKKER, CYRILLE BARTHE´ LE´ MY, PAULE FRACHON, DANIELLE CHATEAU, DAMIEN STERNBERG, JEAN PIERRE MAZAT, AND ANNE LOMBE` S INSERM UR523, Institut de Myologie, 75651 Paris, France [A.B., C.B., P.F., D.C., A.L.]; Biochimie B, Hoˆpital de La Salpeˆtrie`re, 75651 Paris, France [D.S.]; and Universite´ de Bordeaux II, INSERM E99–29, 33076 Bordeaux cedex, France [J.P.M.] ABSTRACT Most mitochondrial DNA (mtDNA) alterations associated wild-type mtDNA, transfer RNA, or protein. Mitochondria in with human disorders are heteroplasmic, i.e. mutant mtDNA these heteroplasmic cells cannot, therefore, be considered a molecules coexist with normal ones within the cell. We ad- single functional unit. (Pediatr Res 48: 143–150, 2000) dressed the possibility of intermitochondrial exchanges through histologic analyses of cybrid clones with increasing proportion of the MELAS (A3243G) mtDNA transfer RNA point mutation. Abbreviations MtDNA-dependent cytochrome c oxidase activity and protein MELAS, mitochondrial myopathy, encephalopathy, lactic composition as well as mitochondrial membrane potential ap- acidosis, and strokelike episodes peared heterogeneous in individual cells from clonal heteroplas-
    [Show full text]
  • Stouthamer1973
    Antonie van Leeuwenhoek 39 (1973) 545-565 545 A theoretical study on the amount of ATP required for synthesis of microbial cell material A. H. STOUTHAMER Biological Laboratory, Free University, de Boelelaan 1087, Amsterdam, the Netherlands STOUTHAMER, A.H. 1973. A theoretical study on the amount of ATP required for synthesis of microbial cell material. Antonie van Leeuwenhoek 39: 545-565. The amount of ATP required for the formation of microbial cells growing under various conditions was calculated. It was assumed that the chemical com­ position of the cell was the same under all these conditions. The analysis of the chemical composition of microbial cells of Morowitz ( 1968) was taken as a base. It was assumed that 4 moles of ATP are required for the incorporation of one mole of amino acid into protein. The amount of ATP required on account of the instability and frequent regeneration of messenger RNA was calculated from data in the literature pertaining to the relative rates of synthesis of the various classes of RNA molecules in the cell. An estimate is given of the amount of ATP required for transport processes. For this purpose it was assumed that 0.5 mole of ATP is necessary for the uptake of 1 g-ion of potassium or ammo­ nium, and 1 mole of ATP for the uptake of 1 mole of phosphate, amino acid, acetate, malate etc. The results of the calculations show that from preformed monomers (glucose, amino acids and nucleic acid bases) 31.9 g cells can be formed per g-mole of ATP when acetyl-CoA is formed from glucose.
    [Show full text]
  • Progressive Increase in Mtdna 3243A>G Heteroplasmy Causes
    Progressive increase in mtDNA 3243A>G PNAS PLUS heteroplasmy causes abrupt transcriptional reprogramming Martin Picarda, Jiangwen Zhangb, Saege Hancockc, Olga Derbenevaa, Ryan Golhard, Pawel Golike, Sean O’Hearnf, Shawn Levyg, Prasanth Potluria, Maria Lvovaa, Antonio Davilaa, Chun Shi Lina, Juan Carlos Perinh, Eric F. Rappaporth, Hakon Hakonarsonc, Ian A. Trouncei, Vincent Procaccioj, and Douglas C. Wallacea,1 aCenter for Mitochondrial and Epigenomic Medicine, Children’s Hospital of Philadelphia and the Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104; bSchool of Biological Sciences, The University of Hong Kong, Hong Kong, People’s Republic of China; cTrovagene, San Diego, CA 92130; dCenter for Applied Genomics, Division of Genetics, Department of Pediatrics, and hNucleic Acid/Protein Research Core Facility, Children’s Hospital of Philadelphia, Philadelphia, PA 19104; eInstitute of Genetics and Biotechnology, Warsaw University, 00-927, Warsaw, Poland; fMorton Mower Central Research Laboratory, Sinai Hospital of Baltimore, Baltimore, MD 21215; gGenomics Sevices Laboratory, HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806; iCentre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC 3002, Australia; and jDepartment of Biochemistry and Genetics, National Center for Neurodegenerative and Mitochondrial Diseases, Centre Hospitalier Universitaire d’Angers, 49933 Angers, France Contributed by Douglas C. Wallace, August 1, 2014 (sent for review May
    [Show full text]
  • A Roadmap for Metagenomic Enzyme Discovery
    Natural Product Reports View Article Online REVIEW View Journal A roadmap for metagenomic enzyme discovery Cite this: DOI: 10.1039/d1np00006c Serina L. Robinson, * Jorn¨ Piel and Shinichi Sunagawa Covering: up to 2021 Metagenomics has yielded massive amounts of sequencing data offering a glimpse into the biosynthetic potential of the uncultivated microbial majority. While genome-resolved information about microbial communities from nearly every environment on earth is now available, the ability to accurately predict biocatalytic functions directly from sequencing data remains challenging. Compared to primary metabolic pathways, enzymes involved in secondary metabolism often catalyze specialized reactions with diverse substrates, making these pathways rich resources for the discovery of new enzymology. To date, functional insights gained from studies on environmental DNA (eDNA) have largely relied on PCR- or activity-based screening of eDNA fragments cloned in fosmid or cosmid libraries. As an alternative, Creative Commons Attribution-NonCommercial 3.0 Unported Licence. shotgun metagenomics holds underexplored potential for the discovery of new enzymes directly from eDNA by avoiding common biases introduced through PCR- or activity-guided functional metagenomics workflows. However, inferring new enzyme functions directly from eDNA is similar to searching for a ‘needle in a haystack’ without direct links between genotype and phenotype. The goal of this review is to provide a roadmap to navigate shotgun metagenomic sequencing data and identify new candidate biosynthetic enzymes. We cover both computational and experimental strategies to mine metagenomes and explore protein sequence space with a spotlight on natural product biosynthesis. Specifically, we compare in silico methods for enzyme discovery including phylogenetics, sequence similarity networks, This article is licensed under a genomic context, 3D structure-based approaches, and machine learning techniques.
    [Show full text]
  • Characterization of Two Cdnas Encoding Mitochondrial Lipoamide Dehydrogenase from Arabidopsis Isabelle Lutziger Iowa State University
    Botany Publication and Papers Botany 10-2001 Characterization of Two cDNAs Encoding Mitochondrial Lipoamide Dehydrogenase from Arabidopsis Isabelle Lutziger Iowa State University David J. Oliver Iowa State University, [email protected] Follow this and additional works at: http://lib.dr.iastate.edu/bot_pubs Part of the Botany Commons Recommended Citation Lutziger, Isabelle and Oliver, David J., "Characterization of Two cDNAs Encoding Mitochondrial Lipoamide Dehydrogenase from Arabidopsis" (2001). Botany Publication and Papers. 1. http://lib.dr.iastate.edu/bot_pubs/1 This Article is brought to you for free and open access by the Botany at Iowa State University Digital Repository. It has been accepted for inclusion in Botany Publication and Papers by an authorized administrator of Iowa State University Digital Repository. For more information, please contact [email protected]. Characterization of Two cDNAs Encoding Mitochondrial Lipoamide Dehydrogenase from Arabidopsis Abstract In contrast to peas (Pisum sativum), where mitochondrial lipoamide dehydrogenase is encoded by a single gene and shared between the α-ketoacid dehydrogenase complexes and the Gly decarboxylase complex, Arabidopsis has two genes encoding for two mitochondrial lipoamide dehydrogenases. Northern-blot analysis revealed different levels of RNA expression for the two genes in different organs; mtLPD1 had higher RNA levels in green leaves compared with the much lower level in roots. The mRNA formtLPD2 shows the inverse pattern. The other organs examined showed nearly equal RNA expressions for both genes. Analysis of etiolated seedlings transferred to light showed a strong induction of RNA expression for mtLPD1 but only a moderate induction of mtLPD2. Based on the organ and light-dependent expression patterns, we hypothesize thatmtLPD1encodes the protein most often associated with the Gly decarboxylase complex, and mtLPD2 encodes the protein incorporated into α-ketoacid dehydrogenase complexes.
    [Show full text]
  • Shared Sulfur Mobilization Routes for Trna Thiolation and Molybdenum Cofactor Biosynthesis in Prokaryotes and Eukaryotes
    biomolecules Review Shared Sulfur Mobilization Routes for tRNA Thiolation and Molybdenum Cofactor Biosynthesis in Prokaryotes and Eukaryotes Silke Leimkühler *, Martin Bühning and Lena Beilschmidt Department of Molecular Enzymology, Institute of Biochemistry and Biology, University of Potsdam, 14476 Potsdam, Germany; [email protected] (M.B.); [email protected] (L.B.) * Correspondence: [email protected]; Tel.: +49-331-977-5603 Academic Editor: Valérie de Crécy-Lagard Received: 8 December 2016; Accepted: 9 January 2017; Published: 14 January 2017 Abstract: Modifications of transfer RNA (tRNA) have been shown to play critical roles in the biogenesis, metabolism, structural stability and function of RNA molecules, and the specific modifications of nucleobases with sulfur atoms in tRNA are present in pro- and eukaryotes. Here, especially the thiomodifications xm5s2U at the wobble position 34 in tRNAs for Lys, Gln and Glu, were suggested to have an important role during the translation process by ensuring accurate deciphering of the genetic code and by stabilization of the tRNA structure. The trafficking and delivery of sulfur nucleosides is a complex process carried out by sulfur relay systems involving numerous proteins, which not only deliver sulfur to the specific tRNAs but also to other sulfur-containing molecules including iron–sulfur clusters, thiamin, biotin, lipoic acid and molybdopterin (MPT). Among the biosynthesis of these sulfur-containing molecules, the biosynthesis of the molybdenum cofactor (Moco) and the synthesis of thio-modified tRNAs in particular show a surprising link by sharing protein components for sulfur mobilization in pro- and eukaryotes. Keywords: tRNA; molybdenum cofactor; persulfide; thiocarboxylate; thionucleosides; sulfurtransferase; L-cysteine desulfurase 1.
    [Show full text]
  • Structural Genomics: an Approach to the Protein Folding Problem
    Commentary Structural genomics: An approach to the protein folding problem Gaetano T. Montelione* Center for Advanced Biotechnology and Medicine, Department of Molecular Biology and Biochemistry, Rutgers University, and Department of Biochemistry, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Piscataway, NJ 08854-5638 he large-scale genome sequencing of information and analyses that will be efficiently determine the phases of the Tprojects present tremendous new op- available as recently funded structural diffraction data required to determine the portunities for structural biology and mo- genomics centers and consortia around protein structure. In this study, MAD was lecular biophysics. This explosion of bio- the world (12–15) come up to speed. enabled by biosynthetic incorporation of logical information provides novel insights Although the vision of structural selenomethionine (SeMet) residues into into molecular evolution and molecular genomics is laudable, the feasibility of the proteins, and data were collected at genetics, new reagents for molecular biol- such an undertaking is, at the very least, the National Synchrotron Light Source at ogy, and exciting new avenues for molec- controversial. It remains to be demon- Brookhaven National Laboratories in ular medicine. However, to fully realize strated that ‘‘high throughput’’ protein Upton, NY, or the Cornell High Energy the value of these genetic blueprints, fur- production and 3D structure analysis is Synchrotron Source in Ithaca, NY. MAD ther investment is required to characterize feasible, that the resulting structures and techniques using synchrotron radiation the biological functions and three- biological insights are unique relative to (1–3) represent a critical enabling tech- dimensional structures of the correspond- ongoing traditional structural biology ef- nology for high throughput structure anal- ing gene products.
    [Show full text]
  • Molecular Basis of Dihydrouridine Formation on Trna
    Molecular basis of dihydrouridine formation on tRNA Futao Yua1, Yoshikazu Tanakab,c1, Keitaro Yamashitaa, Takeo Suzukid, Akiyoshi Nakamurac, Nagisa Hiranoc, Tsutomu Suzukid, Min Yaoa,c, and Isao Tanakaa,c,2 aGraduate School of Life Sciences, Hokkaido University, Sapporo 060-0810, Japan; bCreative Research Institution “Sousei,” Hokkaido University, Sapporo 001-0021, Japan; cFaculty of Advanced Life Sciences, Hokkaido University, Sapporo 060-0810, Japan; and dDepartment of Chemistry and Biotechnology, School of Engineering, University of Tokyo, Tokyo 113-8656, Japan Edited by Dieter Söll, Yale University, New Haven, CT, and approved October 3, 2011 (received for review July 28, 2011) Dihydrouridine (D) is a highly conserved modified base found Similarly, the site specificity and nonredundant catalytic func- in tRNAs from all domains of life. Dihydrouridine synthase (Dus) tions were also confirmed in three Dus from E. coli (YjbN, YhdG, catalyzes the D formation of tRNA through reduction of uracil base and YohI) (8). The crystal structure of Dus from Thermotoga with flavin mononucleotide (FMN) as a cofactor. Here, we report maritima has been reported (9), and mutation analysis of Dus the crystal structures of Thermus thermophilus Dus (TthDus), which from E. coli revealed important residues for dihydrouridine is responsible for D formation at positions 20 and 20a, in complex formation (10). One of the most remarkable biochemical features with tRNA and with a short fragment of tRNA (D-loop). Dus inter- of Dus is that other modifications of tRNA are required for the acts extensively with the D-arm and recognizes the elbow region enzymatic activity (11). However, the details of the reaction, composed of the kissing loop interaction between T- and D-loops in including the tRNA recognition mechanism and its catalysis of tRNA, pulling U20 into the catalytic center for reduction.
    [Show full text]
  • Rrna and Trna Bridges to Neuronal Homeostasis in Health and Disease
    Review rRNA and tRNA Bridges to Neuronal Homeostasis in Health and Disease Francesca Tuorto 1 and Rosanna Parlato 2,3 1 - Division of Epigenetics, DKFZ-ZMBH Alliance, German Cancer Research Center, Im Neuenheimer Feld 580, 69120 Heidelberg, Germany 2 - Institute of Applied Physiology, University of Ulm, Albert Einstein Allee 11, 89081 Ulm, Germany 3 - Institute of Anatomy and Cell Biology, Medical Cell Biology, University of Heidelberg, Im Neuenheimer Feld 307, 69120 Heidelberg, Germany Correspondence to Francesca Tuorto and Rosanna Parlato: German Cancer Research Center, Im Neuenheimer Feld 580, 69120 Heidelberg, Germany. University of Ulm, Institute of Applied Physiology, Albert Einstein Allee, 11, 89081 Ulm, Germany. [email protected], [email protected] https://doi.org/10.1016/j.jmb.2019.03.004 Edited by Ernst Stefan Seemann Abstract Dysregulation of protein translation is emerging as a unifying mechanism in the pathogenesis of many neuronal disorders. Ribosomal RNA (rRNA) and transfer RNA (tRNA) are structural molecules that have complementary and coordinated functions in protein synthesis. Defects in both rRNAs and tRNAs have been described in mammalian brain development, neurological syndromes, and neurodegeneration. In this review, we present the molecular mechanisms that link aberrant rRNA and tRNA transcription, processing and modifications to translation deficits, and neuropathogenesis. We also discuss the interdependence of rRNA and tRNA biosynthesis and how their metabolism brings together proteotoxic stress and impaired neuronal homeostasis. © 2019 Elsevier Ltd. All rights reserved. Introduction at specific positions [4]. There are two main types of tsRNAs: tRNA-derived fragments (tRFs; 14–30 Types of RNA in a eukaryotic cell classically nucleotides) and tiRNAs (tRNA-derived stress- included ribosomal RNA (rRNA), transfer RNA induced RNAs, or tRNA halves, 28–36 nucleotides), (tRNA), and messenger RNA (mRNA).
    [Show full text]
  • Syntenic Gene and Genome Duplication Drives Diversification of Plant Secondary Metabolism and Innate Immunity in Flowering Plants
    Genomics 4.0 - Syntenic Gene and Genome Duplication Drives Diversification of Plant Secondary Metabolism and Innate Immunity in Flowering Plants - Advanced Pattern Analytics in Duplicate Genomes - Johannes A. Hofberger Thesis committee Promotor Prof. Dr M. Eric Schranz Professor of Experimental Biosystematics Wageningen University Other members Prof. Dr Bart P.H.J. Thomma, Wageningen University Prof. Dr Berend Snel, Utrecht University Dr Klaas Vrieling, Leiden University Dr Gabino F. Sanchez, Wageningen University This research was conducted under the auspices of the Graduate School of Experimental Plant Sciences. Genomics 4.0 - Syntenic Gene and Genome Duplication Drives Diversification of Plant Secondary Metabolism and Innate Immunity in Flowering Plants - Advanced Pattern Analytics in Duplicate Genomes - Johannes A. Hofberger Thesis submitted in fulfilment of the requirements for the degree of doctor at Wageningen University by the authority of the Rector Magnificus Prof. Dr M.J. Kropff, in the presence of the Thesis Committee appointed by the Academic Board to be defended in public on Monday 18 May 2015 at 4 p.m. in the Aula. Johannes A. Hofberger Genomics 4.0 - Syntenic Gene and Genome Duplication Drives Diversification of Plant Secondary Metabolism and Innate Immunity in Flowering Plants 83 pages. PhD thesis, Wageningen University, Wageningen, NL (2015) With references, with summaries in Dutch and English ISBN: 978-94-6257-314-7 PROPOSITIONS 1. Ohnolog over-retention following ancient polyploidy facilitated diversification of the glucosinolate biosynthetic inventory in the mustard family. (this thesis) 2. Resistance protein conserved in structurally stable parts of plant genomes confer pleiotropic effects and expanded functions in plant innate immunity. (this thesis) 3.
    [Show full text]
  • Mitochondrial Dysfunction in Parkinson's Disease: Focus on Mitochondrial
    biomedicines Review Mitochondrial Dysfunction in Parkinson’s Disease: Focus on Mitochondrial DNA Olga Buneeva, Valerii Fedchenko, Arthur Kopylov and Alexei Medvedev * Institute of Biomedical Chemistry, 10 Pogodinskaya Street, 119121 Moscow, Russia; [email protected] (O.B.); [email protected] (V.F.); [email protected] (A.K.) * Correspondence: [email protected]; Tel.: +7-495-245-0509 Received: 17 November 2020; Accepted: 8 December 2020; Published: 10 December 2020 Abstract: Mitochondria, the energy stations of the cell, are the only extranuclear organelles, containing their own (mitochondrial) DNA (mtDNA) and the protein synthesizing machinery. The location of mtDNA in close proximity to the oxidative phosphorylation system of the inner mitochondrial membrane, the main source of reactive oxygen species (ROS), is an important factor responsible for its much higher mutation rate than nuclear DNA. Being more vulnerable to damage than nuclear DNA, mtDNA accumulates mutations, crucial for the development of mitochondrial dysfunction playing a key role in the pathogenesis of various diseases. Good evidence exists that some mtDNA mutations are associated with increased risk of Parkinson’s disease (PD), the movement disorder resulted from the degenerative loss of dopaminergic neurons of substantia nigra. Although their direct impact on mitochondrial function/dysfunction needs further investigation, results of various studies performed using cells isolated from PD patients or their mitochondria (cybrids) suggest their functional importance. Studies involving mtDNA mutator mice also demonstrated the importance of mtDNA deletions, which could also originate from abnormalities induced by mutations in nuclear encoded proteins needed for mtDNA replication (e.g., polymerase γ). However, proteomic studies revealed only a few mitochondrial proteins encoded by mtDNA which were downregulated in various PD models.
    [Show full text]