Genetic Analysis of ALS Cases in the Isolated Island Population of Malta
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Computational Genome-Wide Identification of Heat Shock Protein Genes in the Bovine Genome [Version 1; Peer Review: 2 Approved, 1 Approved with Reservations]
F1000Research 2018, 7:1504 Last updated: 08 AUG 2021 RESEARCH ARTICLE Computational genome-wide identification of heat shock protein genes in the bovine genome [version 1; peer review: 2 approved, 1 approved with reservations] Oyeyemi O. Ajayi1,2, Sunday O. Peters3, Marcos De Donato2,4, Sunday O. Sowande5, Fidalis D.N. Mujibi6, Olanrewaju B. Morenikeji2,7, Bolaji N. Thomas 8, Matthew A. Adeleke 9, Ikhide G. Imumorin2,10,11 1Department of Animal Breeding and Genetics, Federal University of Agriculture, Abeokuta, Nigeria 2International Programs, College of Agriculture and Life Sciences, Cornell University, Ithaca, NY, 14853, USA 3Department of Animal Science, Berry College, Mount Berry, GA, 30149, USA 4Departamento Regional de Bioingenierias, Tecnologico de Monterrey, Escuela de Ingenieria y Ciencias, Queretaro, Mexico 5Department of Animal Production and Health, Federal University of Agriculture, Abeokuta, Nigeria 6Usomi Limited, Nairobi, Kenya 7Department of Animal Production and Health, Federal University of Technology, Akure, Nigeria 8Department of Biomedical Sciences, Rochester Institute of Technology, Rochester, NY, 14623, USA 9School of Life Sciences, University of KwaZulu-Natal, Durban, 4000, South Africa 10School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA, 30032, USA 11African Institute of Bioscience Research and Training, Ibadan, Nigeria v1 First published: 20 Sep 2018, 7:1504 Open Peer Review https://doi.org/10.12688/f1000research.16058.1 Latest published: 20 Sep 2018, 7:1504 https://doi.org/10.12688/f1000research.16058.1 Reviewer Status Invited Reviewers Abstract Background: Heat shock proteins (HSPs) are molecular chaperones 1 2 3 known to bind and sequester client proteins under stress. Methods: To identify and better understand some of these proteins, version 1 we carried out a computational genome-wide survey of the bovine 20 Sep 2018 report report report genome. -
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Minor snRNA gene delivery improves the loss of proprioceptive synapses on SMA motor neurons Erkan Y. Osman, … , Livio Pellizzoni, Christian L. Lorson JCI Insight. 2020. https://doi.org/10.1172/jci.insight.130574. Research In-Press Preview Neuroscience Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder caused by reduced expression of the survival motor neuron (SMN) protein. SMN has key functions in multiple RNA pathways, including the biogenesis of small nuclear ribonucleoproteins (snRNPs) that are essential components of both major (U2-dependent) and minor (U12-dependent) spliceosomes. Here we investigated the specific contribution of U12 splicing dysfunction to SMA pathology through selective restoration of this RNA pathway in mouse models of varying phenotypic severity. We show that viral-mediated delivery of minor snRNA genes specifically improves select U12 splicing defects induced by SMN deficiency in cultured mammalian cells as well as in the spinal cord and dorsal root ganglia of SMA mice without increasing SMN expression. This approach resulted in a moderate amelioration of several parameters of the disease phenotype in SMA mice including survival, weight gain and motor function. Importantly, minor snRNA gene delivery improved aberrant splicing of the U12 intron-containing gene Stasimon and rescued the severe loss of proprioceptive sensory synapses on SMA motor neurons, which are early signatures of motor circuit dysfunction in mouse models. Taken together, these findings establish the direct contribution of U12 splicing dysfunction to synaptic deafferentation and motor circuit pathology in SMA. Find the latest version: https://jci.me/130574/pdf Minor snRNA gene delivery improves the loss of proprioceptive synapses on SMA motor neurons Erkan Y. -
Genome-Wide Analyses Identify KIF5A As a Novel ALS Gene
This is a repository copy of Genome-wide Analyses Identify KIF5A as a Novel ALS Gene.. White Rose Research Online URL for this paper: http://eprints.whiterose.ac.uk/129590/ Version: Accepted Version Article: Nicolas, A, Kenna, KP, Renton, AE et al. (210 more authors) (2018) Genome-wide Analyses Identify KIF5A as a Novel ALS Gene. Neuron, 97 (6). 1268-1283.e6. https://doi.org/10.1016/j.neuron.2018.02.027 Reuse This article is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs (CC BY-NC-ND) licence. This licence only allows you to download this work and share it with others as long as you credit the authors, but you can’t change the article in any way or use it commercially. More information and the full terms of the licence here: https://creativecommons.org/licenses/ Takedown If you consider content in White Rose Research Online to be in breach of UK law, please notify us by emailing [email protected] including the URL of the record and the reason for the withdrawal request. [email protected] https://eprints.whiterose.ac.uk/ Genome-wide Analyses Identify KIF5A as a Novel ALS Gene Aude Nicolas1,2, Kevin P. Kenna2,3, Alan E. Renton2,4,5, Nicola Ticozzi2,6,7, Faraz Faghri2,8,9, Ruth Chia1,2, Janice A. Dominov10, Brendan J. Kenna3, Mike A. Nalls8,11, Pamela Keagle3, Alberto M. Rivera1, Wouter van Rheenen12, Natalie A. Murphy1, Joke J.F.A. van Vugt13, Joshua T. Geiger14, Rick A. Van der Spek13, Hannah A. Pliner1, Shankaracharya3, Bradley N. -
Defining Functional Interactions During Biogenesis of Epithelial Junctions
ARTICLE Received 11 Dec 2015 | Accepted 13 Oct 2016 | Published 6 Dec 2016 | Updated 5 Jan 2017 DOI: 10.1038/ncomms13542 OPEN Defining functional interactions during biogenesis of epithelial junctions J.C. Erasmus1,*, S. Bruche1,*,w, L. Pizarro1,2,*, N. Maimari1,3,*, T. Poggioli1,w, C. Tomlinson4,J.Lees5, I. Zalivina1,w, A. Wheeler1,w, A. Alberts6, A. Russo2 & V.M.M. Braga1 In spite of extensive recent progress, a comprehensive understanding of how actin cytoskeleton remodelling supports stable junctions remains to be established. Here we design a platform that integrates actin functions with optimized phenotypic clustering and identify new cytoskeletal proteins, their functional hierarchy and pathways that modulate E-cadherin adhesion. Depletion of EEF1A, an actin bundling protein, increases E-cadherin levels at junctions without a corresponding reinforcement of cell–cell contacts. This unexpected result reflects a more dynamic and mobile junctional actin in EEF1A-depleted cells. A partner for EEF1A in cadherin contact maintenance is the formin DIAPH2, which interacts with EEF1A. In contrast, depletion of either the endocytic regulator TRIP10 or the Rho GTPase activator VAV2 reduces E-cadherin levels at junctions. TRIP10 binds to and requires VAV2 function for its junctional localization. Overall, we present new conceptual insights on junction stabilization, which integrate known and novel pathways with impact for epithelial morphogenesis, homeostasis and diseases. 1 National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London SW7 2AZ, UK. 2 Computing Department, Imperial College London, London SW7 2AZ, UK. 3 Bioengineering Department, Faculty of Engineering, Imperial College London, London SW7 2AZ, UK. 4 Department of Surgery & Cancer, Faculty of Medicine, Imperial College London, London SW7 2AZ, UK. -
Systemic Restoration of UBA1 Ameliorates Disease in Spinal Muscular Atrophy
Systemic restoration of UBA1 ameliorates disease in spinal muscular atrophy Rachael A. Powis, … , Mimoun Azzouz, Thomas H. Gillingwater JCI Insight. 2016;1(11):e87908. https://doi.org/10.1172/jci.insight.87908. Research Article Neuroscience Therapeutics The autosomal recessive neuromuscular disease spinal muscular atrophy (SMA) is caused by loss of survival motor neuron (SMN) protein. Molecular pathways that are disrupted downstream of SMN therefore represent potentially attractive therapeutic targets for SMA. Here, we demonstrate that therapeutic targeting of ubiquitin pathways disrupted as a consequence of SMN depletion, by increasing levels of one key ubiquitination enzyme (ubiquitin-like modifier activating enzyme 1 [UBA1]), represents a viable approach for treating SMA. Loss of UBA1 was a conserved response across mouse and zebrafish models of SMA as well as in patient induced pluripotent stem cell–derive motor neurons. Restoration of UBA1 was sufficient to rescue motor axon pathology and restore motor performance in SMA zebrafish. Adeno- associated virus serotype 9–UBA1 (AAV9-UBA1) gene therapy delivered systemic increases in UBA1 protein levels that were well tolerated over a prolonged period in healthy control mice. Systemic restoration of UBA1 in SMA mice ameliorated weight loss, increased survival and motor performance, and improved neuromuscular and organ pathology. AAV9-UBA1 therapy was also sufficient to reverse the widespread molecular perturbations in ubiquitin homeostasis that occur during SMA. We conclude that UBA1 represents a safe and effective therapeutic target for the treatment of both neuromuscular and systemic aspects of SMA. Find the latest version: https://jci.me/87908/pdf RESEARCH ARTICLE Systemic restoration of UBA1 ameliorates disease in spinal muscular atrophy Rachael A. -
A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated. -
Integrated Transcriptome and Methylome Analysis in Youth at High Risk for Bipolar Disorder: a Preliminary Analysis
OPEN Citation: Transl Psychiatry (2017) 7, e1059; doi:10.1038/tp.2017.32 www.nature.com/tp ORIGINAL ARTICLE Integrated transcriptome and methylome analysis in youth at high risk for bipolar disorder: a preliminary analysis GR Fries1, J Quevedo1,2,3,4, CP Zeni2, IF Kazimi2, G Zunta-Soares2, DE Spiker2, CL Bowden5, C Walss-Bass1,2,3 and JC Soares1,2 First-degree relatives of patients with bipolar disorder (BD), particularly their offspring, have a higher risk of developing BD and other mental illnesses than the general population. However, the biological mechanisms underlying this increased risk are still unknown, particularly because most of the studies so far have been conducted in chronically ill adults and not in unaffected youth at high risk. In this preliminary study we analyzed genome-wide expression and methylation levels in peripheral blood mononuclear cells from children and adolescents from three matched groups: BD patients, unaffected offspring of bipolar parents (high risk) and controls (low risk). By integrating gene expression and DNA methylation and comparing the lists of differentially expressed genes and differentially methylated probes between groups, we were able to identify 43 risk genes that discriminate patients and high-risk youth from controls. Pathway analysis showed an enrichment of the glucocorticoid receptor (GR) pathway with the genes MED1, HSPA1L, GTF2A1 and TAF15, which might underlie the previously reported role of stress response in the risk for BD in vulnerable populations. Cell-based assays indicate a GR hyporesponsiveness in cells from adult BD patients compared to controls and suggest that these GR-related genes can be modulated by DNA methylation, which poses the theoretical possibility of manipulating their expression as a means to counteract the familial risk presented by those subjects. -
Mitochondrial Heat Shock Protein 60: Evaluation of Its Role As a Neuroprotectant in Familial ALS and Its Mutation As a Cause of Hereditary Spastic Paraplegia
Mitochondrial Heat Shock Protein 60: Evaluation of its role as a neuroprotectant in familial ALS and its mutation as a cause of hereditary spastic paraplegia By Laura A. Cooper Integrated Program in Neuroscience McGill University, Montreal June 2011 A thesis submitted to McGill University in partial fulfillment of the requirements of the degree of master’s in science © Laura A. Cooper, 2011 TABLE OF CONTENTS ABSTRACT…………………………………………………………………………….vi RÉSUMÉ……………………………………………………………………………….viii ACKNOWLEDGMENTS……………………………………………………………..xi LIST OF FIGURES……………………………………………………………………xiii ABBREVIATIONS………………………………………………………………….....xv INTRODUCTION……………………………………………………………………..xx CHAPTER 1 – Literature Review 1.1 Amyotrophic Lateral Sclerosis 1.1.1 Clinical Overview..................................................................................................1 1.1.2 Sporadic ALS…………………………………………………………………….2 1.1.3 Familial ALS……………………………………………………………………..4 1.1.4 Cu/Zn Superoxide Dismutase Mutation and fALS……………………………….4 1.1.5 Protein Aggregation in SOD1-Related fALS…………………………………….5 1.1.6 Mitochondrial Abnormalities in Mouse Models of SOD1-Related fALS………..7 1.1.7 Relationship Between Mutant SOD1 and Mitochondrial Abnormalities………..8 1.2 Heat Shock Proteins 1.2.1 Normal Function in the Central Nervous System and Relevance to ALS……….9 1.2.2 Heat Shock Proteins as a Therapeutic Target in ALS………………………….10 1.3 Mitochondrial Heat Shock Protein Hsp60 1.3.1 Structure and Function………………………………………………………....12 ii 1.3.2 Mitochondrial Hsp60 in Neuroprotection……………………………………. -
Analysis of Shared Common Genetic Risk Between Amyotrophic Lateral Sclerosis and Epilepsy
Neurobiology of Aging xxx (2020) 1.e1e1.e5 Contents lists available at ScienceDirect Neurobiology of Aging journal homepage: www.elsevier.com/locate/neuaging Negative results Analysis of shared common genetic risk between amyotrophic lateral sclerosis and epilepsy Dick Schijvena,b,c, Remi Stevelinkd, Mark McCormackd,e, Wouter van Rheenena, Jurjen J. Luykxb, Bobby P.C. Koelemand, Jan H. Veldinka,*, on behalf of the Project MinE ALS GWAS Consortium International League Against Epilepsy Consortium on Complex Epilepsies a Department of Neurology and Neurosurgery, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands b Department of Psychiatry, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands c Department of Translational Neuroscience, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands d Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands e Department of Molecular and Cellular Therapeutics, The Royal College of Surgeons in Ireland, Dublin, Ireland article info abstract Article history: Because hyper-excitability has been shown to be a shared pathophysiological mechanism, we used the Received 23 September 2019 latest and largest genome-wide studies in amyotrophic lateral sclerosis (n ¼ 36,052) and epilepsy (n ¼ Received in revised form 31 January 2020 38,349) to determine genetic overlap between these conditions. First, we showed no significant ge- Accepted 10 April 2020 netic correlation, also when binned on minor allele frequency. Second, we confirmed the absence of polygenic overlap using genomic risk score analysis. Finally, we did not identify pleiotropic variants in meta-analyses of the 2 diseases. -
Supplementary Table S1. Correlation Between the Mutant P53-Interacting Partners and PTTG3P, PTTG1 and PTTG2, Based on Data from Starbase V3.0 Database
Supplementary Table S1. Correlation between the mutant p53-interacting partners and PTTG3P, PTTG1 and PTTG2, based on data from StarBase v3.0 database. PTTG3P PTTG1 PTTG2 Gene ID Coefficient-R p-value Coefficient-R p-value Coefficient-R p-value NF-YA ENSG00000001167 −0.077 8.59e-2 −0.210 2.09e-6 −0.122 6.23e-3 NF-YB ENSG00000120837 0.176 7.12e-5 0.227 2.82e-7 0.094 3.59e-2 NF-YC ENSG00000066136 0.124 5.45e-3 0.124 5.40e-3 0.051 2.51e-1 Sp1 ENSG00000185591 −0.014 7.50e-1 −0.201 5.82e-6 −0.072 1.07e-1 Ets-1 ENSG00000134954 −0.096 3.14e-2 −0.257 4.83e-9 0.034 4.46e-1 VDR ENSG00000111424 −0.091 4.10e-2 −0.216 1.03e-6 0.014 7.48e-1 SREBP-2 ENSG00000198911 −0.064 1.53e-1 −0.147 9.27e-4 −0.073 1.01e-1 TopBP1 ENSG00000163781 0.067 1.36e-1 0.051 2.57e-1 −0.020 6.57e-1 Pin1 ENSG00000127445 0.250 1.40e-8 0.571 9.56e-45 0.187 2.52e-5 MRE11 ENSG00000020922 0.063 1.56e-1 −0.007 8.81e-1 −0.024 5.93e-1 PML ENSG00000140464 0.072 1.05e-1 0.217 9.36e-7 0.166 1.85e-4 p63 ENSG00000073282 −0.120 7.04e-3 −0.283 1.08e-10 −0.198 7.71e-6 p73 ENSG00000078900 0.104 2.03e-2 0.258 4.67e-9 0.097 3.02e-2 Supplementary Table S2. -
Value of Systematic Genetic Screening of Patients with Amyotrophic Lateral
Neurodegeneration J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2020-325014 on 14 February 2021. Downloaded from Original research Value of systematic genetic screening of patients with amyotrophic lateral sclerosis Stephanie R Shepheard ,1 Matthew D Parker,1 Johnathan Cooper- Knock ,1 Nick S Verber,1 Lee Tuddenham,1 Paul Heath,1 Nick Beauchamp,2 Elsie Place,2 Elizabeth S A Sollars,2 Martin R Turner ,3 Andrea Malaspina,4 Pietro Fratta,5,6 Channa Hewamadduma,7 Thomas M Jenkins ,1 Christopher J McDermott ,1 Dennis Wang,8 Janine Kirby,1 Pamela J Shaw ,1,7 on behalf of the Project MINE Consortium ► Additional material is ABSTRACT mild cognitive impairment, with approximately published online only. To view, Objective The clinical utility of routine genetic 5% progressing to clinically recognised fronto- please visit the journal online 1 (http:// dx. doi. org/ 10. 1136/ sequencing in amyotrophic lateral sclerosis (ALS) is temporal dementia (FTD). While the majority of jnnp- 2020- 325014). uncertain. Our aim was to determine whether routine ALS cases are considered sporadic (sALS), 5%–10% targeted sequencing of 44 ALS- relevant genes would have been shown to be familial, usually with auto- For numbered affiliations see have a significant impact on disease subclassification somal dominant inheritance, and the genetic cause end of article. and clinical care. of approximately 60%–70% of familial ALS (fALS) 2 Methods We performed targeted sequencing of a 44- cases has now been identified. The most common Correspondence to Professor Pamela J Shaw, gene panel in a prospective case series of 100 patients genetic cause of ALS is due to expansion of a Sheffield Institute for with ALS recruited consecutively from the Sheffield GGGGCC (G4C2) hexanucleotide repeat in the Translational Neuroscience, The Motor Neuron Disorders Clinic, UK. -
The Ubiquitin Proteasome System in Neuromuscular Disorders: Moving Beyond Movement
International Journal of Molecular Sciences Review The Ubiquitin Proteasome System in Neuromuscular Disorders: Moving Beyond Movement 1, , 2, 3,4 Sara Bachiller * y , Isabel M. Alonso-Bellido y , Luis Miguel Real , Eva María Pérez-Villegas 5 , José Luis Venero 2 , Tomas Deierborg 1 , José Ángel Armengol 5 and Rocío Ruiz 2 1 Experimental Neuroinflammation Laboratory, Department of Experimental Medical Science, Lund University, Sölvegatan 19, 221 84 Lund, Sweden; [email protected] 2 Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla/Instituto de Biomedicina de Sevilla-Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, 41012 Sevilla, Spain; [email protected] (I.M.A.-B.); [email protected] (J.L.V.); [email protected] (R.R.) 3 Unidad Clínica de Enfermedades Infecciosas, Hospital Universitario de Valme, 41014 Sevilla, Spain; [email protected] 4 Departamento de Especialidades Quirúrgicas, Bioquímica e Inmunología, Facultad de Medicina, 29071 Universidad de Málaga, Spain 5 Departamento de Fisiología, Anatomía y Biología Celular, Universidad Pablo de Olavide, 41013 Sevilla, Spain; [email protected] (E.M.P.-V.); [email protected] (J.Á.A.) * Correspondence: [email protected] These authors contributed equally to the work. y Received: 14 July 2020; Accepted: 31 August 2020; Published: 3 September 2020 Abstract: Neuromuscular disorders (NMDs) affect 1 in 3000 people worldwide. There are more than 150 different types of NMDs, where the common feature is the loss of muscle strength. These disorders are classified according to their neuroanatomical location, as motor neuron diseases, peripheral nerve diseases, neuromuscular junction diseases, and muscle diseases. Over the years, numerous studies have pointed to protein homeostasis as a crucial factor in the development of these fatal diseases.