Genetic Analysis of Multiple System Atrophy and Related Movement Disorders
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The Contributions of Microglial Vps35 to Adult Hippocampal Neurogenesis and Neurodegenerative Disorders
THE CONTRIBUTIONS OF MICROGLIAL VPS35 TO ADULT HIPPOCAMPAL NEUROGENESIS AND NEURODEGENERATIVE DISORDERS By Joanna Ruth Erion Submitted to the Faculty of the Graduate School of Augusta University in partial fulfillment of the Requirements of the Degree of Doctor of Philosophy April 2017 COPYRIGHT© 2017 by Joanna Ruth Erion THE CONTRIBUTIONS OF MICROGLIAL VPS35 TO ADULT HIPPOCAMPAL NEUROGENESIS AND NEURODEGENERATIVE DISORDERS This thesis/dissertation is submitted by Joanna Ruth Erion and has been examined and approved by an appointed committee of the faculty of the Graduate School of Augusta University. The signatures which appear below verify the fact that all required changes have been incorporated and that the thesis/dissertation has received final approval with reference to content, form and accuracy of presentation. This thesis/dissertation is therefore in partial fulfillment of the requirements for the degree of Doctor of Philosophy). ___________________ __________________________________ Date Major Advisor __________________________________ Departmental Chairperson __________________________________ Dean, Graduate School ACKNOWLEDGEMENTS I will be forever grateful to my mentor, Dr. Wen-Cheng Xiong, for welcoming me into her laboratory and providing me with the honor and opportunity to work under her astute leadership. I have learned many valuable lessons under her guidance, all of which have enabled me to grow as both a student and a scientist. It was with her erudite guidance and suggestions that I was able to examine aspects of my investigations that I had yet to consider and ask questions that would not have otherwise occurred to me. I would also like to thank Dr. Lin Mei for contributing not only his laboratory and resources to my endeavors, but also his guidance and input into my investigations, providing me with additional avenues for directing my efforts. -
Role of Amylase in Ovarian Cancer Mai Mohamed University of South Florida, [email protected]
University of South Florida Scholar Commons Graduate Theses and Dissertations Graduate School July 2017 Role of Amylase in Ovarian Cancer Mai Mohamed University of South Florida, [email protected] Follow this and additional works at: http://scholarcommons.usf.edu/etd Part of the Pathology Commons Scholar Commons Citation Mohamed, Mai, "Role of Amylase in Ovarian Cancer" (2017). Graduate Theses and Dissertations. http://scholarcommons.usf.edu/etd/6907 This Dissertation is brought to you for free and open access by the Graduate School at Scholar Commons. It has been accepted for inclusion in Graduate Theses and Dissertations by an authorized administrator of Scholar Commons. For more information, please contact [email protected]. Role of Amylase in Ovarian Cancer by Mai Mohamed A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy Department of Pathology and Cell Biology Morsani College of Medicine University of South Florida Major Professor: Patricia Kruk, Ph.D. Paula C. Bickford, Ph.D. Meera Nanjundan, Ph.D. Marzenna Wiranowska, Ph.D. Lauri Wright, Ph.D. Date of Approval: June 29, 2017 Keywords: ovarian cancer, amylase, computational analyses, glycocalyx, cellular invasion Copyright © 2017, Mai Mohamed Dedication This dissertation is dedicated to my parents, Ahmed and Fatma, who have always stressed the importance of education, and, throughout my education, have been my strongest source of encouragement and support. They always believed in me and I am eternally grateful to them. I would also like to thank my brothers, Mohamed and Hussien, and my sister, Mariam. I would also like to thank my husband, Ahmed. -
Parkinson's Disease Causative Mutation in Vps35 Disturbs Tetherin
cells Article Parkinson’s Disease Causative Mutation in Vps35 Disturbs Tetherin Trafficking to Cell Surfaces and Facilitates Virus Spread Yingzhuo Ding 1,†, Yan Li 1,† , Gaurav Chhetri 1 , Xiaoxin Peng 1, Jing Wu 1, Zejian Wang 1, Bo Zhao 1 , Wenjuan Zhao 1 and Xueyi Li 1,2,* 1 School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China; [email protected] (Y.D.); [email protected] (Y.L.); [email protected] (G.C.); [email protected] (X.P.); [email protected] (J.W.); [email protected] (Z.W.); [email protected] (B.Z.); [email protected] (W.Z.) 2 Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA * Correspondence: [email protected] or [email protected] † These authors contributed equally to this work. Abstract: Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, characterized by progressive loss of dopaminergic neurons in the substantia nigra, intraneuronal deposition of misfolded proteins known as Lewy bodies, and chronic neuroinflammation. PD can arise from monogenic mutations, but in most cases, the etiology is unclear. Viral infection is gaining increasing attentions as a trigger of PD. In this study, we investigated whether the PD-causative Citation: Ding, Y.; Li, Y.; Chhetri, G.; 620 aspartate (D) to asparagine (N) mutation in the vacuolar protein sorting 35 ortholog (Vps35) Peng, X.; Wu, J.; Wang, Z.; Zhao, B.; precipitated herpes simplex virus (HSV) infection. We observed that ectopic expression of Vps35 Zhao, W.; Li, X. Parkinson’s Disease significantly reduced the proliferation and release of HSV-1 virions; the D620N mutation rendered Causative Mutation in Vps35 Vps35 a partial loss of such inhibitory effects. -
Retromer Deficiency Observed in Alzheimer's Disease Causes
Retromer deficiency observed in Alzheimer’s disease causes hippocampal dysfunction, neurodegeneration, and A accumulation Alim Muhammad*, Ingrid Flores*, Hong Zhang*†, Rui Yu*, Agnieszka Staniszewski*†, Emmanuel Planel*†, Mathieu Herman*†, Lingling Ho‡, Robert Kreber‡, Lawrence S. Honig*§, Barry Ganetzky‡¶, Karen Duff*†, Ottavio Arancio*†, and Scott A. Small*§¶ *Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, and Departments of §Neurology and †Pathology, Columbia University College of Physicians and Surgeons, New York, NY 10032; and ‡Laboratory of Genetics, University of Wisconsin, Madison, WI 53706-1580 Contributed by Barry Ganetzky, March 13, 2008 (sent for review December 2, 2007) Although deficiencies in the retromer sorting pathway have been ␥-secretase, it was important to investigate retromer deficiency linked to late-onset Alzheimer’s disease, whether these deficien- on a nonmutated genetic background. To determine whether cies underlie the disease remains unknown. Here we characterized retromer deficiency causes hippocampal dysfunction, a key two genetically modified animal models to test separate but clinical feature of Alzheimer’s disease, we began by investigating related questions about the effects that retromer deficiency has on retromer deficiency in genetically modified mice. Our results the brain. First, testing for cognitive defects, we investigated suggest that retromer deficiency causes hippocampal dysfunction retromer-deficient mice and found that they develop hippocampal- by elevating concentrations of endogenous A peptide. dependent memory and synaptic dysfunction, which was associ- Although APP and BACE are highly homologous across species, ated with elevations in endogenous A peptide. Second, testing important sequence differences do exist, and these differences can for neurodegeneration and amyloid deposits, we investigated affect their intracellular transport, APP processing, and the neu- retromer-deficient flies expressing human wild-type amyloid pre- rotoxicity of APP end products (12). -
Appendix 2. Significantly Differentially Regulated Genes in Term Compared with Second Trimester Amniotic Fluid Supernatant
Appendix 2. Significantly Differentially Regulated Genes in Term Compared With Second Trimester Amniotic Fluid Supernatant Fold Change in term vs second trimester Amniotic Affymetrix Duplicate Fluid Probe ID probes Symbol Entrez Gene Name 1019.9 217059_at D MUC7 mucin 7, secreted 424.5 211735_x_at D SFTPC surfactant protein C 416.2 206835_at STATH statherin 363.4 214387_x_at D SFTPC surfactant protein C 295.5 205982_x_at D SFTPC surfactant protein C 288.7 1553454_at RPTN repetin solute carrier family 34 (sodium 251.3 204124_at SLC34A2 phosphate), member 2 238.9 206786_at HTN3 histatin 3 161.5 220191_at GKN1 gastrokine 1 152.7 223678_s_at D SFTPA2 surfactant protein A2 130.9 207430_s_at D MSMB microseminoprotein, beta- 99.0 214199_at SFTPD surfactant protein D major histocompatibility complex, class II, 96.5 210982_s_at D HLA-DRA DR alpha 96.5 221133_s_at D CLDN18 claudin 18 94.4 238222_at GKN2 gastrokine 2 93.7 1557961_s_at D LOC100127983 uncharacterized LOC100127983 93.1 229584_at LRRK2 leucine-rich repeat kinase 2 HOXD cluster antisense RNA 1 (non- 88.6 242042_s_at D HOXD-AS1 protein coding) 86.0 205569_at LAMP3 lysosomal-associated membrane protein 3 85.4 232698_at BPIFB2 BPI fold containing family B, member 2 84.4 205979_at SCGB2A1 secretoglobin, family 2A, member 1 84.3 230469_at RTKN2 rhotekin 2 82.2 204130_at HSD11B2 hydroxysteroid (11-beta) dehydrogenase 2 81.9 222242_s_at KLK5 kallikrein-related peptidase 5 77.0 237281_at AKAP14 A kinase (PRKA) anchor protein 14 76.7 1553602_at MUCL1 mucin-like 1 76.3 216359_at D MUC7 mucin 7, -
Alzheimer's Disease
VU Research Portal Spot the difference Bossers, C.A.M. 2009 document version Publisher's PDF, also known as Version of record Link to publication in VU Research Portal citation for published version (APA) Bossers, C. A. M. (2009). Spot the difference: microarray analysis of gene expression changes in Alzheimer's and Parkinson's Disease. General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal ? Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. E-mail address: [email protected] Download date: 11. Oct. 2021 Spot the difference: microarray analysis of gene expression changes in Alzheimer’s and Parkinson’s Disease The research described in this thesis was conducted at the Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sci- ences, Amsterdam, The Netherlands. The research was financially supported by a collaboration between the Netherlands Institute for Neuroscience and Solvay Phar- maceuticals. Leescommissie: dr. -
Parkinson's Disease-Linked D620N VPS35 Knockin Mice Manifest Tau
Parkinson’s disease-linked D620N VPS35 knockin mice manifest tau neuropathology and dopaminergic neurodegeneration Xi Chena, Jennifer K. Kordicha, Erin T. Williamsa, Nathan Levinea, Allyson Cole-Straussb, Lee Marshalla, Viviane Labriea,c, Jiyan Maa, Jack W. Liptonb, and Darren J. Moorea,1 aCenter for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI 49503; bDepartment of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI 49503; and cDivision of Psychiatry and Behavioral Medicine, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503 Edited by Anders Björklund, Lund University, Lund, Sweden, and approved February 13, 2019 (received for review August 30, 2018) Mutations in the vacuolar protein sorting 35 ortholog (VPS35) since only a single D620N mutation carrier has been evaluated at gene represent a cause of late-onset, autosomal dominant familial autopsy but with the notable exception of key PD-relevant brain Parkinson’s disease (PD). A single missense mutation, D620N, is regions (i.e., substantia nigra, locus ceruleus, or any brainstem considered pathogenic based upon its segregation with disease area) (7). Outside of these areas, VPS35 mutation carriers lack in multiple families with PD. At present, the mechanism(s) by extranigral α-synuclein–positive Lewy body pathology (7), a which familial VPS35 mutations precipitate neurodegeneration in characteristic hallmark of PD brains. The mechanism by which PD are poorly understood. Here, we employ a germline D620N dominantly inherited mutations in VPS35 induce neuropathology VPS35 knockin (KI) mouse model of PD to formally establish the and neurodegeneration in PD remains enigmatic. age-related pathogenic effects of the D620N mutation at physiolog- VPS35 encodes a core component of the retromer complex, ical expression levels. -
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 -
Persistent Transcription-Blocking DNA Lesions Trigger Somatic Growth Attenuation Associated with Longevity
ARTICLES Persistent transcription-blocking DNA lesions trigger somatic growth attenuation associated with longevity George A. Garinis1,2, Lieneke M. Uittenboogaard1, Heike Stachelscheid3,4, Maria Fousteri5, Wilfred van Ijcken6, Timo M. Breit7, Harry van Steeg8, Leon H. F. Mullenders5, Gijsbertus T. J. van der Horst1, Jens C. Brüning4,9, Carien M. Niessen3,9,10, Jan H. J. Hoeijmakers1 and Björn Schumacher1,9,11 The accumulation of stochastic DNA damage throughout an organism’s lifespan is thought to contribute to ageing. Conversely, ageing seems to be phenotypically reproducible and regulated through genetic pathways such as the insulin-like growth factor-1 (IGF-1) and growth hormone (GH) receptors, which are central mediators of the somatic growth axis. Here we report that persistent DNA damage in primary cells from mice elicits changes in global gene expression similar to those occurring in various organs of naturally aged animals. We show that, as in ageing animals, the expression of IGF-1 receptor and GH receptor is attenuated, resulting in cellular resistance to IGF-1. This cell-autonomous attenuation is specifically induced by persistent lesions leading to stalling of RNA polymerase II in proliferating, quiescent and terminally differentiated cells; it is exacerbated and prolonged in cells from progeroid mice and confers resistance to oxidative stress. Our findings suggest that the accumulation of DNA damage in transcribed genes in most if not all tissues contributes to the ageing-associated shift from growth to somatic maintenance that triggers stress resistance and is thought to promote longevity. Ageing represents the progressive functional decline that is exempted levels as a result of pituitary dysfunction (Snell and Ames mice) — have an from evolutionary selection because it largely occurs after reproduc- extended lifespan17–20. -
The Genetic Architecture of Parkinson's Disease
Review The genetic architecture of Parkinson’s disease Cornelis Blauwendraat, Mike A Nalls, Andrew B Singleton Lancet Neurol 2020; 19: 170–78 Parkinson’s disease is a complex neurodegenerative disorder for which both rare and common genetic variants Published Online contribute to disease risk, onset, and progression. Mutations in more than 20 genes have been associated with the September 11, 2019 disease, most of which are highly penetrant and often cause early onset or atypical symptoms. Although our http://dx.doi.org/10.1016/ understanding of the genetic basis of Parkinson’s disease has advanced considerably, much remains to be done. S1474-4422(19)30287-X Further disease-related common genetic variability remains to be identified and the work in identifying rare risk Laboratory of Neurogenetics, National Institute on Aging, alleles has only just begun. To date, genome-wide association studies have identified 90 independent risk-associated National Institutes of Health, variants. However, most of them have been identified in patients of European ancestry and we know relatively little of Bethesda, MD, USA the genetics of Parkinson’s disease in other populations. We have a limited understanding of the biological functions (C Blauwendraat PhD, of the risk alleles that have been identified, although Parkinson’s disease risk variants appear to be in close proximity M A Nalls PhD, A B Singleton PhD); and Data to known Parkinson’s disease genes and lysosomal-related genes. In the past decade, multiple efforts have been made Tecnica International, to investigate the genetic architecture of Parkinson’s disease, and emerging technologies, such as machine learning, Glen Echo, MD, USA (M A Nalls) single-cell RNA sequencing, and high-throughput screens, will improve our understanding of genetic risk. -
Aldrich Syndrome Protein: Emerging Mechanisms in Immunity
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by UCL Discovery Wiskott-Aldrich syndrome protein: emerging mechanisms in immunity E Rivers1 and AJ Thrasher1 1 UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London, WC1N 1EH Correspondence: [email protected] Key words Autoimmunity, immune synapse, inflammation, Wiskott Aldrich syndrome, Wiskott Aldrich syndrome protein Summary The Wiskott Aldrich syndrome protein (WASP) participates in innate and adaptive immunity through regulation of actin cytoskeleton-dependent cellular processes, including immune synapse formation, cell signaling, migration and cytokine release. There is also emerging evidence for a direct role in nuclear transcription programmes uncoupled from actin polymerization. A deeper understanding of some of the more complex features of Wiskott Aldrich syndrome (WAS) itself, such as the associated autoimmunity and inflammation, has come from identification of defects in the number and function of anti-inflammatory myeloid cells and regulatory T and B cells, as well as defects in positive and negative B-cell selection. In this review we outline the cellular defects that have been characterized in both human WAS patients and murine models of the disease. We will emphasize in particular recent discoveries that provide a mechanistic insight into disease pathology, including lymphoid and myeloid cell homeostasis, immune synapse assembly and immune cell signaling. Received: 22/03/2017; Revised: 10/07/2017; Accepted: 09/08/2017 This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. -
Arginine to Glutamine Mutation in Olfactomedin Like 3 (OLFML3) Is a Candidate for Severe
bioRxiv preprint doi: https://doi.org/10.1101/321406; this version posted July 25, 2018. 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 Arginine to glutamine mutation in olfactomedin like 3 (OLFML3) is a candidate for severe 2 goniodysgenesis and glaucoma in the Border Collie dog breed. 3 4 Carys A Pugh*, Lindsay L Farrell* 1, Ailsa J Carlisle*, Stephen J Bush*†, Violeta Trejo- 5 Reveles*, Oswald Matika*, Arne de Kloet‡, Caitlin Walsh‡, Stephen C Bishop* 2, James GD 6 Prendergast*, Jeffrey J Schoenebeck*, Joe Rainger*, Kim M Summers*§ 7 8 * The Roslin Institute, Easter Bush EH25 9RG, United Kingdom 9 † Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, 10 Oxford OX3 9DU, United Kingdom 11 ‡ Animal Genetics, 1336 Timberlane Rd, Tallahassee, FL 32312, USA 12 § Mater Research Institute-UQ, Translational Research Institute, Brisbane, Qld 4012, 13 Australia 14 1 Present address: British Columbia Centre on Substance Abuse, St Paul’s Hospital, 15 Vancouver, BC V6Z 1Y6, Canada 16 2 Deceased 17 18 1 bioRxiv preprint doi: https://doi.org/10.1101/321406; this version posted July 25, 2018. 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. 19 Running title: OLFML3 mutation in Border Collie glaucoma 20 21 Key words: Glaucoma, goniodysgenesis, olfactomedin like 3, Border Collie, eye development 22 23 Corresponding authors: 24 Dr Carys Pugh, The Roslin Institute, University of Edinburgh, Easter Bush EH25 9RG, UK 25 Phone: +441316519221 26 Email: [email protected] 27 Professor Kim M Summers, Mater Research Institute-UQ, Translational Research Institute, 28 37 Kent St, Woolloongabba, QLD 4102, Australia 29 Phone: +61734437655 30 Email: [email protected] 2 bioRxiv preprint doi: https://doi.org/10.1101/321406; this version posted July 25, 2018.