DOCSLIB.ORG

Characterization and Treatment of a Novel Mouse Model of Tsc-Associated Autism

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Characterization and Treatment of a Novel Mouse Model of Tsc-Associated Autism The Texas Medical Center Library DigitalCommons@TMC The University of Texas MD Anderson Cancer Center UTHealth Graduate School of The University of Texas MD Anderson Cancer Biomedical Sciences Dissertations and Theses Center UTHealth Graduate School of (Open Access) Biomedical Sciences 8-2012 CHARACTERIZATION AND TREATMENT OF A NOVEL MOUSE MODEL OF TSC-ASSOCIATED AUTISM Rachel Michelle Reith Follow this and additional works at: https://digitalcommons.library.tmc.edu/utgsbs_dissertations Part of the Medicine and Health Sciences Commons Recommended Citation Reith, Rachel Michelle, "CHARACTERIZATION AND TREATMENT OF A NOVEL MOUSE MODEL OF TSC- ASSOCIATED AUTISM" (2012). The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access). 266. https://digitalcommons.library.tmc.edu/utgsbs_dissertations/266 This Dissertation (PhD) is brought to you for free and open access by the The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences at DigitalCommons@TMC. It has been accepted for inclusion in The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access) by an authorized administrator of DigitalCommons@TMC. For more information, please contact [email protected]. CHARACTERIZATION AND TREATMENT OF A NOVEL MOUSE MODEL OF TSC-ASSOCIATED AUTISM by Rachel Michelle Reith, B.S. APPROVED: ______________________________ Michael J. Gambello, M.D., Ph.D., Supervisory Professor ______________________________ Pramod Dash, Ph.D. ______________________________ Raymond J. Grill, Ph.D. ______________________________ Gilbert J. Cote, Ph.D. ______________________________ Cheryl L. Walker, Ph.D. ______________________________ Dos D. Sarbassov, Ph.D. APPROVED: ____________________________ Dean, The University of Texas Graduate School of Biomedical Sciences at Houston i CHARACTERIZATION AND TREATMENT OF A NOVEL MOUSE MODEL OF TSC-ASSOCIATED AUTISM A DISSERTATION Presented to the Faculty of The University of Texas Health Science Center at Houston and The University of Texas M. D. Anderson Cancer Center Graduate School of Biomedical Sciences in Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY by Rachel Michelle Reith, B.S. Houston, Texas August 2012 ii “You will be enriched in every way so that you can be generous on every occasion, and though us your generosity will result in thanksgiving to God.” 2 Corinthians 9:11 iii Acknowledgements Isaac Newton once said “if I have seen further than others, it is by standing upon the shoulders of giants.” My success would not have been possible without these giants in my own life. First, I have to thank my Lord and Savior, Jesus Christ. This is more for me, because you already know my thoughts. Psalm 139:2 says “You know when I sit and when I rise; you perceive my thoughts from afar.” Philippians 4:13 says: “I can do all this through him who gives me strength.” Thank you for your strength, for without it I am nothing. I give you the glory. Thank you also for your love. Romans 8:38-39 says “For I am convinced that neither death nor life, neither angels nor demons, neither the present nor the future, nor any powers, neither height nor depth, nor anything else in all creation, will be able to separate us from the love of God that is in Christ Jesus our Lord.” Next, I want to thank Dr. Gambello. I can’t even fully express what you mean to me. You have challenged me in so many ways. I know that I exasperate you at times, but I hope that you have seen me bear fruit. I have grown as a scientist and a person under your leadership. Thank you also for the balance of independence and guidance. You were there to guide me when I needed, but you also allowed me to develop as an independent scientist. I will carry on your legacy. Thank you to my lab mates: Sharon Way, Jim McKenna, and Henry Wu. Your work formed the foundation of my studies. You have also helped me in this project in many ways. You covered my injections so I could take a much needed break or go on interviews. But you also gave me so much advice, guidance, and definitely some laughs. Thank you to my committee members (Pramod Dash, Ray Grill, Gil Cote, Cheryl Walker, and Dos Sarbassov). You have given me a lot of helpful advice over the years. However, your vote of confidence means the most to me. Thank you for even trying to make me graduate earlier! Thank you Dr. Dash for taking over as my “chair” after Dr. Gambello departed. Thank you both to Dr. Cote and Dr. Grill for your personal and scientific advice. I have always felt that your doors were open for me to come with questions. iv Thank you Dr. Northrup and Dr. Filipek for allowing me to shadow in clinic. Seeing patients with both TSC and autism have really helped me in my heart for researching these disorders. It is great to put a human perspective on my mouse model. Thank you also to Dr. Northrup for speaking opportunities to share my work with families and patients with TSC. Thank you to both the Center for Clinical and Translational Science program and the Schissler family for your generous support. Truly, this research would not have been possible without you. Thank you Meagan Walker and Jennifer Dulin for your helpful suggestions on my dissertation. Thank you to those who got me interested in science and helped me to develop as a scientist. Particularly to my undergraduate research advisor, Dr. Beckingham, who allowed me to explore my own hypothesis. Making that project “my own” was my first step in developing as a true scientist. Thank you Dr. Carolyn Smith. The promise of a great post doc position in your lab has kept me going in these final months of stress. I look forward to our research together. To the mice. Oh, the hours I tortured you. Thank you for not biting me…much. Thank you for giving your life to the pursuit of science. Thank you to the pediatrics IT department. How many hours of your time were consumed with my endless computer problems? Thank you for your patience and help dealing with them. Now, we will have to go and find a roof to throw that computer off one of these days. Thank you to my dad. You have taught me what it is to work hard in life. I do not believe that I would be where I am today without your influence and certainly not without your support. Thank you to my mom. You are more my friend than anything. Thank you for dealing with me while I have been stressed out and taking care of what was necessary. Thank you for offering to help me watch mouse videos. Thank you for arranging everything for our celebration. Thank you for so much more. v Thank you to Cameron Jeter for being a voice of encouragement as someone who has done this before. I am so happy for our friendship. To all of my family and friends. Many of you have taken time out of your days to be at my defense. But more than that, you have taken time out of your lives to invest in mine. I cannot measure the effect you have had on me. Nor can I conceive of how much I will miss you when I move. Thank you to Teahouse. You knew my order and had my drink made before I even checked out. Without you, I would have been much less caffeinated. I also need to thank my cat. Not only did you help me watch hours of mouse videos, but you even wanted more! vi CHARACTERIZATION AND TREATMENT OF A NOVEL MOUSE MODEL OF TSC- ASSOCIATED AUTISM Publication No.________* Rachel Michelle Reith, B.S. Supervisory Professor: Michael J. Gambello, M.D., Ph.D. Tuberous sclerosis complex (TSC) is a dominant tumor suppressor disorder caused by mutations in either TSC1 or TSC2. The proteins of these genes form a complex to inhibit the mammalian target of rapamycin complex 1 (mTORC1), which controls protein translation and cell growth. TSC causes substantial neuropathology, often leading to autism spectrum disorders (ASDs) in up to 60% of patients. The anatomic and neurophysiologic links between these two disorders are not well understood. However, both disorders share cerebellar abnormalities. Therefore, we have characterized a novel mouse model in which the Tsc2 gene was selectively deleted from cerebellar Purkinje cells (Tsc2f/-;Cre). These mice exhibit progressive Purkinje cell degeneration. Since loss of Purkinje cells is a well-reported postmortem finding in patients with ASD, we conducted a series of behavior tests to assess if Tsc2f/-;Cre mice displayed autistic-like deficits. Using the three chambered social choice assay, we found that Tsc2f/-;Cre mice showed behavioral deficits, exhibiting no preference between a stranger mouse and an inanimate object, or between a novel and a familiar mouse. Tsc2f/-;Cre mice also demonstrated increased repetitive behavior as assessed with marble burying activity. Altogether, these results demonstrate that loss of Tsc2 in Purkinje cells in a haploinsufficient background lead to behavioral deficits that are characteristic of human autism. Therefore, Purkinje cells loss and/or dysfunction may be an important link between TSC and ASD. Additionally, we have examined some of the cellular mechanisms resulting from mutations in Tsc2 leading to Purkinje cell death. Loss of Tsc2 led to upregulation of vii mTORC1 and increased cell size. As a consequence of increased protein synthesis, several cellular stress pathways were upregulated. Principally, these included altered calcium signaling, oxidative stress, and ER stress. Likely as a consequence of ER stress, there was also upregulation of ubiquitin and autophagy.
Load more

Recommended publications
  • 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.
    [Show full text]
  • Cldn19 Clic2 Clmp Cln3
    NewbornDx™ Advanced Sequencing Evaluation When time to diagnosis matters, the NewbornDx™ Advanced Sequencing Evaluation from Athena Diagnostics delivers rapid, 5- to 7-day results on a targeted 1,722-genes. A2ML1 ALAD ATM CAV1 CLDN19 CTNS DOCK7 ETFB FOXC2 GLUL HOXC13 JAK3 AAAS ALAS2 ATP1A2 CBL CLIC2 CTRC DOCK8 ETFDH FOXE1 GLYCTK HOXD13 JUP AARS2 ALDH18A1 ATP1A3 CBS CLMP CTSA DOK7 ETHE1 FOXE3 GM2A HPD KANK1 AASS ALDH1A2 ATP2B3 CC2D2A CLN3 CTSD DOLK EVC FOXF1 GMPPA HPGD K ANSL1 ABAT ALDH3A2 ATP5A1 CCDC103 CLN5 CTSK DPAGT1 EVC2 FOXG1 GMPPB HPRT1 KAT6B ABCA12 ALDH4A1 ATP5E CCDC114 CLN6 CUBN DPM1 EXOC4 FOXH1 GNA11 HPSE2 KCNA2 ABCA3 ALDH5A1 ATP6AP2 CCDC151 CLN8 CUL4B DPM2 EXOSC3 FOXI1 GNAI3 HRAS KCNB1 ABCA4 ALDH7A1 ATP6V0A2 CCDC22 CLP1 CUL7 DPM3 EXPH5 FOXL2 GNAO1 HSD17B10 KCND2 ABCB11 ALDOA ATP6V1B1 CCDC39 CLPB CXCR4 DPP6 EYA1 FOXP1 GNAS HSD17B4 KCNE1 ABCB4 ALDOB ATP7A CCDC40 CLPP CYB5R3 DPYD EZH2 FOXP2 GNE HSD3B2 KCNE2 ABCB6 ALG1 ATP8A2 CCDC65 CNNM2 CYC1 DPYS F10 FOXP3 GNMT HSD3B7 KCNH2 ABCB7 ALG11 ATP8B1 CCDC78 CNTN1 CYP11B1 DRC1 F11 FOXRED1 GNPAT HSPD1 KCNH5 ABCC2 ALG12 ATPAF2 CCDC8 CNTNAP1 CYP11B2 DSC2 F13A1 FRAS1 GNPTAB HSPG2 KCNJ10 ABCC8 ALG13 ATR CCDC88C CNTNAP2 CYP17A1 DSG1 F13B FREM1 GNPTG HUWE1 KCNJ11 ABCC9 ALG14 ATRX CCND2 COA5 CYP1B1 DSP F2 FREM2 GNS HYDIN KCNJ13 ABCD3 ALG2 AUH CCNO COG1 CYP24A1 DST F5 FRMD7 GORAB HYLS1 KCNJ2 ABCD4 ALG3 B3GALNT2 CCS COG4 CYP26C1 DSTYK F7 FTCD GP1BA IBA57 KCNJ5 ABHD5 ALG6 B3GAT3 CCT5 COG5 CYP27A1 DTNA F8 FTO GP1BB ICK KCNJ8 ACAD8 ALG8 B3GLCT CD151 COG6 CYP27B1 DUOX2 F9 FUCA1 GP6 ICOS KCNK3 ACAD9 ALG9
    [Show full text]
  • 2021 Code Changes Reference Guide
    Boston University Medical Group 2021 CPT Code Changes Reference Guide Page 1 of 51 Background Current Procedural Terminology (CPT) was created by the American Medical Association (AMA) in 1966. It is designed to be a means of effective and dependable communication among physicians, patients, and third-party payers. CPT provides a uniform coding scheme that accurately describes medical, surgical, and diagnostic services. CPT is used for public and private reimbursement systems; development of guidelines for medical care review; as a basis for local, regional, and national utilization comparisons; and medical education and research. CPT Category I codes describe procedures and services that are consistent with contemporary medical practice. Category I codes are five-digit numeric codes. CPT Category II codes facilitate data collection for certain services and test results that contribute to positive health outcomes and quality patient care. These codes are optional and used for performance management. They are alphanumeric five-digit codes with the alpha character F in the last position. CPT Category III codes represent emerging technologies. They are alphanumeric five-digit codes with the alpha character T in the last position. The CPT Editorial Panel, appointed by the AMA Board of Trustees, is responsible for maintaining and updating the CPT code set. Purpose The AMA makes annual updates to the CPT code set, effective January 1. These updates include deleted codes, revised codes, and new codes. It’s important for providers to understand the code changes and the impact those changes will have to systems, workflow, reimbursement, and RVUs. This document is meant to assist you with this by providing a summary of the changes; a detailed breakdown of this year’s CPT changes by specialty, and HCPCS Updates for your reference.
    [Show full text]
  • 158273472.Pdf
    ANNUAL .2003REPCOLD SPRING HARBOR LABORATORY .1; ANNUAL REPORT 2003 © 2004 by Cold Spring Harbor Laboratory Cold Spring Harbor Laboratory One Bungtown Road Cold Spring Harbor, New York 11724 Web Site: www.cshl.edu Managing Editors Jeff Picarello, Lisa Becker Production Editor Rena Steuer Copy Editor Dorothy Brown Development Manager Jan Argentine Project Coordinators Maria Falasca, Nora Rice Production Manager Denise Weiss Desktop Editor Susan Schaefer Nonscientific Photography Miriam Chua, Bill Geddes Cover Designer Denise Weiss Book Designer Emily Harste Front cover: McClintock Laboratory (right) and Carnegie Library (left) (photos by Miriam Chua) Back cover: Magnolia Kobus on grounds of Cold Spring Harbor Laboratory (photo by Bruce Stillman) Section title pages: Miriam Chua Contents Officers of the Corporation/Board of Trusteesiv-v Governancevi Committees vii Edwin Marks (1926-2003) viii PRESIDENT'S REPORT Highlights5 CHIEF OPERATING OFFICER'S REPORT 25 50TH ANNIVERSARY OF THE DOUBLE HELIX 29 RESEARCH 47 Cancer: Gene Expression 49 Cancer: Genetics 74 Cancer: Cell Biology 106 Bioinformatics and Genomics 134 Neuroscience152 Plant Development and Genetics 199 CSHL Fellows 212 Author Index 217 WATSON SCHOOL OF BIOLOGICAL SCIENCES 219 Dean's Report 221 Courses 238 Undergraduate Research Program245 Partners for the Future 248 Nature Study 249 COLD SPRING HARBOR LABORATORY MEETINGS AND COURSES 251 Academic Affairs253 Symposium on Quantitative Biology 255 Meetings 258 Postgraduate Courses295 Seminars 353 BANBURY CENTER 355 Director's Report357 Meetings 365 DOLAN DNA LEARNING CENTER 403 Director's Report 405 Workshops, Meetings, and Collaborations 418 COLD SPRING HARBOR LABORATORY PRESS 425 Publications 426 Executive Director's Report 427 FINANCE 431 History of the CSHL Endowment 433 Financial Statements 444 Financial Support448 Grants448 Institutional Advancement 457 Capital and Program Contributions 458 Watson School of Biological Sciences Capital Campaign 459 Annual Contributions 460 LABORATORY STAFF 474 III Officers of the Corporation William R.
    [Show full text]
  • A Set of Regulatory Genes Co-Expressed in Embryonic Human Brain Is Implicated in Disrupted Speech Development
    Molecular Psychiatry https://doi.org/10.1038/s41380-018-0020-x ARTICLE A set of regulatory genes co-expressed in embryonic human brain is implicated in disrupted speech development 1 1 1 2 3 Else Eising ● Amaia Carrion-Castillo ● Arianna Vino ● Edythe A. Strand ● Kathy J. Jakielski ● 4,5 6 7 8 9 Thomas S. Scerri ● Michael S. Hildebrand ● Richard Webster ● Alan Ma ● Bernard Mazoyer ● 1,10 4,5 6,11 6,12 13 Clyde Francks ● Melanie Bahlo ● Ingrid E. Scheffer ● Angela T. Morgan ● Lawrence D. Shriberg ● Simon E. Fisher 1,10 Received: 22 September 2017 / Revised: 3 December 2017 / Accepted: 2 January 2018 © The Author(s) 2018. This article is published with open access Abstract Genetic investigations of people with impaired development of spoken language provide windows into key aspects of human biology. Over 15 years after FOXP2 was identified, most speech and language impairments remain unexplained at the molecular level. We sequenced whole genomes of nineteen unrelated individuals diagnosed with childhood apraxia of speech, a rare disorder enriched for causative mutations of large effect. Where DNA was available from unaffected parents, CHD3 SETD1A WDR5 fi 1234567890();,: we discovered de novo mutations, implicating genes, including , and . In other probands, we identi ed novel loss-of-function variants affecting KAT6A, SETBP1, ZFHX4, TNRC6B and MKL2, regulatory genes with links to neurodevelopment. Several of the new candidates interact with each other or with known speech-related genes. Moreover, they show significant clustering within a single co-expression module of genes highly expressed during early human brain development. This study highlights gene regulatory pathways in the developing brain that may contribute to acquisition of proficient speech.
    [Show full text]
  • Elucidating Biological Roles of Novel Murine Genes in Hearing Impairment in Africa
    Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 19 September 2019 doi:10.20944/preprints201909.0222.v1 Review Elucidating Biological Roles of Novel Murine Genes in Hearing Impairment in Africa Oluwafemi Gabriel Oluwole,1* Abdoulaye Yal 1,2, Edmond Wonkam1, Noluthando Manyisa1, Jack Morrice1, Gaston K. Mazanda1 and Ambroise Wonkam1* 1Division of Human Genetics, Department of Pathology, Faculty of Health Sciences, University of Cape Town, Observatory, Cape Town, South Africa. 2Department of Neurology, Point G Teaching Hospital, University of Sciences, Techniques and Technology, Bamako, Mali. *Correspondence to: [email protected]; [email protected] Abstract: The prevalence of congenital hearing impairment (HI) is highest in Africa. Estimates evaluated genetic causes to account for 31% of HI cases in Africa, but the identification of associated causative genes mutations have been challenging. In this study, we reviewed the potential roles, in humans, of 38 novel genes identified in a murine study. We gathered information from various genomic annotation databases and performed functional enrichment analysis using online resources i.e. genemania and g.proflier. Results revealed that 27/38 genes are express mostly in the brain, suggesting additional cognitive roles. Indeed, HERC1- R3250X had been associated with intellectual disability in a Moroccan family. A homozygous 216-bp deletion in KLC2 was found in two siblings of Egyptian descent with spastic paraplegia. Up to 27/38 murine genes have link to at least a disease, and the commonest mode of inheritance is autosomal recessive (n=8). Network analysis indicates that 20 other genes have intermediate and biological links to the novel genes, suggesting their possible roles in HI.
    [Show full text]
  • Human Induced Pluripotent Stem Cell–Derived Podocytes Mature Into Vascularized Glomeruli Upon Experimental Transplantation
    BASIC RESEARCH www.jasn.org Human Induced Pluripotent Stem Cell–Derived Podocytes Mature into Vascularized Glomeruli upon Experimental Transplantation † Sazia Sharmin,* Atsuhiro Taguchi,* Yusuke Kaku,* Yasuhiro Yoshimura,* Tomoko Ohmori,* ‡ † ‡ Tetsushi Sakuma, Masashi Mukoyama, Takashi Yamamoto, Hidetake Kurihara,§ and | Ryuichi Nishinakamura* *Department of Kidney Development, Institute of Molecular Embryology and Genetics, and †Department of Nephrology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan; ‡Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Hiroshima, Japan; §Division of Anatomy, Juntendo University School of Medicine, Tokyo, Japan; and |Japan Science and Technology Agency, CREST, Kumamoto, Japan ABSTRACT Glomerular podocytes express proteins, such as nephrin, that constitute the slit diaphragm, thereby contributing to the filtration process in the kidney. Glomerular development has been analyzed mainly in mice, whereas analysis of human kidney development has been minimal because of limited access to embryonic kidneys. We previously reported the induction of three-dimensional primordial glomeruli from human induced pluripotent stem (iPS) cells. Here, using transcription activator–like effector nuclease-mediated homologous recombination, we generated human iPS cell lines that express green fluorescent protein (GFP) in the NPHS1 locus, which encodes nephrin, and we show that GFP expression facilitated accurate visualization of nephrin-positive podocyte formation in
    [Show full text]
  • 1 Fibrillar Αβ Triggers Microglial Proteome Alterations and Dysfunction in Alzheimer Mouse 1 Models 2 3 4 Laura Sebastian
    bioRxiv preprint doi: https://doi.org/10.1101/861146; this version posted December 2, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 Fibrillar triggers microglial proteome alterations and dysfunction in Alzheimer mouse 2 models 3 4 5 Laura Sebastian Monasor1,10*, Stephan A. Müller1*, Alessio Colombo1, Jasmin König1,2, Stefan 6 Roth3, Arthur Liesz3,4, Anna Berghofer5, Takashi Saito6,7, Takaomi C. Saido6, Jochen Herms1,4,8, 7 Michael Willem9, Christian Haass1,4,9, Stefan F. Lichtenthaler 1,4,5# & Sabina Tahirovic1# 8 9 1 German Center for Neurodegenerative Diseases (DZNE) Munich, 81377 Munich, Germany 10 2 Faculty of Chemistry, Technical University of Munich, Garching, Germany 11 3 Institute for Stroke and Dementia Research (ISD), Ludwig-Maximilians Universität München, 12 81377 Munich, Germany 13 4 Munich Cluster for Systems Neurology (SyNergy), Munich, Germany 14 5 Neuroproteomics, School of Medicine, Klinikum Rechts der Isar, Technical University of Munich, 15 Munich, Germany 16 6 Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science Institute, Wako, 17 Saitama 351-0198, Japan 18 7 Department of Neurocognitive Science, Nagoya City University Graduate School of Medical 19 Science, Nagoya, Aichi 467-8601, Japan 20 8 Center for Neuropathology and Prion Research, Ludwig-Maximilians-Universität München, 81377 21 Munich, Germany 22 9 Biomedical Center (BMC), Ludwig-Maximilians Universität München, 81377 Munich, Germany 23 10 Graduate School of Systemic Neuroscience, Ludwig-Maximilians-University Munich, Munich, 24 Germany. 25 *Contributed equally 26 #Correspondence: [email protected] and [email protected] 27 28 Running title: 29 Microglial proteomic signatures of AD 30 Keywords: Alzheimer’s disease / microglia / proteomic signatures / neuroinflammation / 31 phagocytosis 32 1 bioRxiv preprint doi: https://doi.org/10.1101/861146; this version posted December 2, 2019.
    [Show full text]
  • Protein Symbol Protein Name Rank Metric Score 4F2 4F2 Cell-Surface
    Supplementary Table 2 Supplementary Table 2. Ranked list of proteins present in anti-Sema4D treated macrophage conditioned media obtained in the GSEA analysis of the proteomic data. Proteins are listed according to their rank metric score, which is the score used to position the gene in the ranked list of genes of the GSEA. Values are obtained from comparing Sema4D treated RAW conditioned media versus REST, which includes untreated, IgG treated and anti-Sema4D added RAW conditioned media. GSEA analysis was performed under standard conditions in November 2015. Protein Rank metric symbol Protein name score 4F2 4F2 cell-surface antigen heavy chain 2.5000 PLOD3 Procollagen-lysine,2-oxoglutarate 5-dioxygenase 3 1.4815 ELOB Transcription elongation factor B polypeptide 2 1.4350 ARPC5 Actin-related protein 2/3 complex subunit 5 1.2603 OSTF1 teoclast-stimulating factor 1 1.2500 RL5 60S ribomal protein L5 1.2135 SYK Lysine--tRNA ligase 1.2135 RL10A 60S ribomal protein L10a 1.2135 TXNL1 Thioredoxin-like protein 1 1.1716 LIS1 Platelet-activating factor acetylhydrolase IB subunit alpha 1.1067 A4 Amyloid beta A4 protein 1.0911 H2B1M Histone H2B type 1-M 1.0514 UB2V2 Ubiquitin-conjugating enzyme E2 variant 2 1.0381 PDCD5 Programmed cell death protein 5 1.0373 UCHL3 Ubiquitin carboxyl-terminal hydrolase isozyme L3 1.0061 PLEC Plectin 1.0061 ITPA Inine triphphate pyrophphatase 0.9524 IF5A1 Eukaryotic translation initiation factor 5A-1 0.9314 ARP2 Actin-related protein 2 0.8618 HNRPL Heterogeneous nuclear ribonucleoprotein L 0.8576 DNJA3 DnaJ homolog subfamily
    [Show full text]
  • The Genetics of Intellectual Disability: Whole Exome Sequencing to Find Causative Variants in Severe Cases
    Master’s Project in Medicine No 4362 The Genetics of Intellectual Disability: whole exome sequencing to find causative variants in severe cases Student Winteler Florence Supervisor Prof. Reymond Alexandre, Ph.D. Center for Integrative Genomics, UNIL Co-Supervisor Gueneau Lucie, Ph.D. Center for Integrative Genomics, UNIL Expert Prof. Draganski Bogdan, Dr. méd Département des neurosciences cliniques, CHUV Lausanne, 25.11.2017 Abstract Intellectual disability (ID) affects 1-3% of the population. A genetic origin is estimated to account for about half of the currently undiagnosed cases, and despite recent successes in identifying some of the genes, it has been suggested that hundreds more genes remain to be identified. ID can be isolated or part of a more complex clinical picture –indeed other symptoms are often found in patients with severe genetic ID, such as developmental delay, organ malformations or seizures. In this project, we used whole exome sequencing (WES) to analyse the coding regions of the genes (exons) of patients with undiagnosed ID and that of their families. The variants called by our algorithm were then grossly sorted out using criteria such as frequency in the general population and predicted pathogenicity. A second round of selection was made by looking at the relevant literature about the function of the underlying genes and pathways involved. The selected variants were then Sanger-sequenced for confirmation. This strategy allowed us to find the causative variant and give a diagnosis to the first family we analysed, as the patient was carrying a mutation in the Methyl-CpG binding protein 2 gene (MECP2), already known to cause Rett syndrome.
    [Show full text]
  • Figure S1. GO Analysis of Genes in Glioblastoma Cases That Showed Positive and Negative Correlations with TCIRG1 in the GSE16011 Cohort
    Figure S1. GO analysis of genes in glioblastoma cases that showed positive and negative correlations with TCIRG1 in the GSE16011 cohort. (A‑C) GO‑BP, GO‑CC and GO‑MF terms of genes that showed positive correlations with TCIRG1, respec‑ tively. (D‑F) GO‑BP, GO‑CC and GO‑MF terms of genes that showed negative correlations with TCIRG1. Red nodes represent gene counts, and black bars represent negative 1og10 P‑values. TCIRG1, T cell immune regulator 1; GO, Gene Ontology; BP, biological process; CC, cellular component; MF, molecular function. Table SI. Genes correlated with T cell immune regulator 1. Gene Name Pearson's r ARPC1B Actin‑related protein 2/3 complex subunit 1B 0.756 IL4R Interleukin 4 receptor 0.695 PLAUR Plasminogen activator, urokinase receptor 0.693 IFI30 IFI30, lysosomal thiol reductase 0.675 TNFAIP3 TNF α‑induced protein 3 0.675 RBM47 RNA binding motif protein 47 0.666 TYMP Thymidine phosphorylase 0.665 CEBPB CCAAT/enhancer binding protein β 0.663 MVP Major vault protein 0.660 BCL3 B‑cell CLL/lymphoma 3 0.657 LILRB3 Leukocyte immunoglobulin‑like receptor B3 0.656 ELF4 E74 like ETS transcription factor 4 0.652 ITGA5 Integrin subunit α 5 0.651 SLAMF8 SLAM family member 8 0.647 PTPN6 Protein tyrosine phosphatase, non‑receptor type 6 0.641 RAB27A RAB27A, member RAS oncogene family 0.64 S100A11 S100 calcium binding protein A11 0.639 CAST Calpastatin 0.638 EHBP1L1 EH domain‑binding protein 1‑like 1 0.638 LILRB2 Leukocyte immunoglobulin‑like receptor B2 0.629 ALDH3B1 Aldehyde dehydrogenase 3 family member B1 0.626 GNA15 G protein
    [Show full text]
  • Weighted Burden Analysis of Exome-Sequenced Case-Control Sample Implicates Synaptic Genes in Schizophrenia Aetiology
    Behavior Genetics (2018) 48:198–208 https://doi.org/10.1007/s10519-018-9893-3 ORIGINAL RESEARCH Weighted Burden Analysis of Exome-Sequenced Case-Control Sample Implicates Synaptic Genes in Schizophrenia Aetiology David Curtis1,2 · Leda Coelewij1 · Shou‑Hwa Liu1 · Jack Humphrey1,3 · Richard Mott1 Received: 22 November 2017 / Accepted: 13 March 2018 / Published online: 21 March 2018 © The Author(s) 2018 Abstract A previous study of exome-sequenced schizophrenia cases and controls reported an excess of singleton, gene-disruptive vari- ants among cases, concentrated in particular gene sets. The dataset included a number of subjects with a substantial Finnish contribution to ancestry. We have reanalysed the same dataset after removal of these subjects and we have also included non- singleton variants of all types using a weighted burden test which assigns higher weights to variants predicted to have a greater effect on protein function. We investigated the same 31 gene sets as previously and also 1454 GO gene sets. The reduced dataset consisted of 4225 cases and 5834 controls. No individual variants or genes were significantly enriched in cases but 13 out of the 31 gene sets were significant after Bonferroni correction and the “FMRP targets” set produced a signed log p value (SLP) of 7.1. The gene within this set with the highest SLP, equal to 3.4, was FYN, which codes for a tyrosine kinase which phosphorylates glutamate metabotropic receptors and ionotropic NMDA receptors, thus modulating their trafficking, subcellular distribution and function. In the most recent GWAS of schizophrenia it was identified as a “prioritized candidate gene”.
    [Show full text]