DOCSLIB.ORG

Thesis Reference

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

Thesis Proteomic analysis of the substantia nigra in patients with Parkinson's disease LICKER, Virginie Abstract The specific cascade of biological events underlying substantia nigra neurodegeneration in Parkinson's disease (PD) remains elusive. To gain new insights into PD pathogenesis, we conducted some proteomic investigations of nigral autopsy tissues from patients with PD and controls. Our approach highlighted a set of proteins differentially expressed in PD. A majority of them such as CNDP2 or nebulette were novel candidates potentially engaged in PD pathological process. Overall, observed alterations tended to confirm well accepted concepts surrounding PD pathogenesis but also pointed out the involvement of less conventional ones such as ER stress, cytoskeleton or extracellular matrix impairments. This project provides further insights into PD pathogenesis and may ultimately help to delineate new therapeutic targets and biomarkers for the treatment and diagnosis of PD. Reference LICKER, Virginie. Proteomic analysis of the substantia nigra in patients with Parkinson's disease. Thèse de doctorat : Univ. Genève, 2013, no. Sc. 4532 URN : urn:nbn:ch:unige-333777 DOI : 10.13097/archive-ouverte/unige:33377 Available at: http://archive-ouverte.unige.ch/unige:33377 Disclaimer: layout of this document may differ from the published version. 1 / 1 UNIVERSITE DE GENEVE Département des Sciences des Protéines Humaines FACULTE DE MEDECINE Professeur P.R. Burkhard Section des Sciences Pharmaceutiques FACULTE DES SCIENCES Professeur D.F. Hochstrasser Proteomic Analysis of the Substantia Nigra in Patients with Parkinson’s Disease THESE Présentée à la Faculté des Sciences de l’Université de Genève pour obtenir le grade de Docteur ès Sciences, mention interdisciplinaire par Virginie Licker de Chermignon (VS) Thèse n°4532 Genève 2013 REMERCIEMENTS J’aimerais exprimer toute ma gratitude à ceux qui ont d’une façon ou d’une autre contribué à la réalisation de cette thèse. Aux membres du Jury, Prof. François Berger et Dr Christian Wider pour avoir accepté de lire et d’évaluer mon travail de thèse. Aux Prof. Pierre Burkhard et Denis Hochstrasser, directeur et co-directeur de thèse, qui m’ont permis d’évoluer au sein de leur laboratoire. Merci à Pierre de m’avoir encouragée à participer à des congrès internationaux de qualité, ainsi que pour la grande liberté laissée au cours de ces quatre ans qui m’a permis de gagner en indépendance scientifique. Au Prof. Jean-Charles Sanchez, pour m’avoir aidée à avancer et à me surpasser durant ces quatre années au travers de discussions scientifiques ainsi que par ses commentaires et relectures critiques. Son dynamisme, son enthousiasme et sa disponibilité auront été des moteurs essentiels. Au Dr Natacha Turck, pour son soutien autant scientifique que moral, pour ses commentaires pertinents quel que soit le sujet ainsi que pour sa « positive attitude ». Aux neuropathologues, les Dr. Alexander Lobrinus, Karim Burkhardt et Enikö Kovari dont la collaboration a permis la collecte des échantillons de substance noire. Un merci particulier à Enikö pour sa disponibilité, sa gentillesse et ses conseils, ainsi qu’à Maria Surini pour toute son aide sur la partie IHC. A Mélanie Côte, ma collègue, pour son aide et savoir-faire apportés tout au long de cette thèse. Ainsi que pour ses incroyables pâtisseries dont mes papilles se souviendront longtemps. A tous les membres du BPRG pour leur soutien au quotidien. A mes collègues doctorants, Natalia, Domitille, Didia, Xavier, Hui-Song, Florent, Francesco, ainsi qu’Alex (« &Co ») et Vanessa, ainsi qu’aux nouveaux venus Leire, Florian et Cindy. Merci pour votre soutien scientifique, votre solidarité mais aussi pour tous les bons moments passés ensemble, au labo ou en soirée, congrès et voyage! Qui aurait pu croire qu’un jour Harry, William, Prince Philip ou encore Victoria B s’inviteraient au BPRG… A Anne et Lisa, co-Queens of Sciences, avec qui j’ai beaucoup ri et partagé les petits soucis du quotidien comme les grandes questions existentielles. Ensemble nous avons appris à relativiser. Plutôt que de se préoccuper d’un projet voué à « s’effondrer » - les derniers WB, TMT ou IF ne fonctionnant pas, il est parfois préférable de se concentrer sur la subtile différence entre un Waikiki Orange et un Cajun Schrimp. Je n’arrive toujours pas à croire que j’ai réussi à vous faire participer à la course de l’Escalade, je l’écris pour la postérité. A mes princesses préférées Dany, Loyse, Auré, Vaness R, Jo, Steph, Olivia et la belle Amel. Merci pour tous ces précieux moments entre copines qui m’ont permis de déconnecter de mon doctorat. Merci de m’avoir écoutée et soutenue!! Le voyage à Barcelone fut une véritable bouffée d’oxygène durant ce dernier été « haletant ». A mes chers amis Louise, Lorric, Vaness P, Caro et David. Merci d’être toujours là depuis si longtemps. Un clin d’œil à deux de mes amis et prédécesseurs qui manquent cruellement au CMU, Lucie et Lorenzo! A Andrée, pour son inébranlable bonne humeur et gentillesse qui font de ma leçon de piano hebdomadaire un moment de détente incontournable depuis tant d’années. A Kim, pour m’avoir écoutée et soutenue à certains moments difficiles de ma thèse ainsi que pour être l’un des seuls à connaître mon sujet de thèse. A mes adorables manoriens Harris, Nat, Anais, Loichot, Béatrice, mais aussi Tatjana. Un remerciement particulier à Béa pour ne douter que rarement du bien-fondé de mes plaintes en tout genre et pour être toujours si bon public. A Nicolas, pour avoir mis un peu de Cassis, de Mouse, de Muse et de Mousse dans cette dernière phase d’écriture. A mes parents, mes grands-parents et à mon frère pour leurs encouragements et leur amour. Un merci tout particulier à Greg pour son irrésistible sens de l’humour et de la répartie: rien de tel qu’un bon fou rire pour oublier les soucis de la thèse... à toi de jouer maintenant, courage ! TABLE OF CONTENTS ABBREVIATIONS …………….…………………………….………………………………………………………………………. p. 3 ABSTRACT………..…..…………………………………………………………………………………………………………….... p. 5 RÉSUMÉ………..…..…………………………………………………………………………………………………………......... p. 7 CHAPTER I : GENERAL INTRODUCTION 1. Description of Parkinson’s disease…...………………………….…………………………………………... p. 11 1.1. Historical background.………………………………………………………………………………….. p. 11 1.1.1. PD in Ancient Times .………………………………………………………………………… p. 11 1.1.2. The first clinical definition of PD…………………………………………………………… p. 12 1.1.3. PD pathology ………………………………………………………………………..…………… p. 13 1.1.4. The miracle of levodopa …………………………..…………………………..…………… p. 14 1.2. Epidemiology: prevalence, incidence and socioeconomic aspects.………………. p. 15 1.3. Clinical description.…...……….....…………………………………………………………………… p. 16 1.3.1. Motor and non-motor symptoms………………………………………………………. p. 16 1.3.2. PD progression and rating scales……………………………………………………….. p. 17 1.4. Diagnosis.……………………………………………………………………………………………………… p. 19 1.5. Treatment…….………………………….…………………………………………………………………… p. 21 2. Etiopathogenesis of Parkinson’s disease…………………………………………………………………... p. 24 2.1. PD pathology ………………………………………………………………………………..……………… p. 23 2.1.1. The nigrostriatal pathway and the dopaminergic system…………………… p. 24 2.1.1.1. Anatomy and function of the basal ganglia…………………………….. p. 24 2.1.1.2. PD pathophysiology ………………………………………..…………………….. p. 25 2.1.1.3. Neuropathological hallmarks……………………………………….………… p. 27 2.1.2. Beyond the substantia nigra………………………………………..…………………….. p. 29 2.1.3. Braak staging of PD………………………………………..……………………….………….. p. 30 2.1.4. PD progression: a prion-like hypothesis? ……….…………………..…………….. p. 32 2.2. Risk factors and etiological hypotheses PD pathology …………………………….…… p. 34 2.2.1. Non-genetic risk factors……….……………………………………………..…………….. p. 34 2.2.2. Genetic risk factors……….…………………..……………………………………………….. p. 35 2.2.2.1. PD causative genes……….…………………..………………………………..….. p. 35 2.2.2.2. Susceptibility genes……….…………………..………………………………….. p. 36 2.3. Pathogenetic mechanisms of PD ……………………………………………………………….… p. 37 2.3.1. The specific vulnerability of nigral dopaminergic neurons…………………… p. 38 2.3.2. Potential mechanisms underlying neurodegeneration……………………… p. 39 2.3.2.1. Alpha-synuclein, Lewy bodies and protein aggregation………… p. 39 2.3.2.2. Impairment of protein degradation systems………………………….. p. 40 2.3.2.2.1. Ubiquitin proteasome system………………………………….... p. 41 1 2.3.2.2.2. Lysosome and chaperone mediated autophagy………… p. 42 2.3.2.3. Mitochondria and oxidative stress…………………………………….….. p. 45 2.3.2.4. Glial reaction and inflammation…………………………………….………. p. 47 3. Proteomics and Parkinson’s disease research………………………………………………………………. p. 51 3.1. “omics and PD research …………………………………………………………………………….. p. 51 3.2. Proteomics ………………………….…………………………………………………………………….. p. 53 3.2.1. Generalities…………………………………….…………………………………..…. p. 53 3.2.2. Sample preparation…………………………………….…………………………. p. 55 3.2.3. Sample separation…………………………………….…………………………… p. 56 3.2.4. Mass spectrometry and bioinformatics………………………….………. p. 58 3.2.5. Quantitative proteomics…………………………………………….….………. p. 60 4. Project presentation and aims……………………………………………………………………………………… p. 64 5. Bibliography…………………………………………………………………………………………………………………... p. 66 CHAPTER II: Proteomics in human Parkinson's disease research ……………………………………… p.81 CHAPTER III: Neuroproteomics and Parkinson’s disease: don’t forget human samples ……… p. 103 CHAPTER IV: Proteomic profiling of the substantia nigra demonstrates CNDP2 overexpression in Parkinson's disease………………………………………………………….. p. 109 CHAPTER V: Human substantia nigra proteomics: insights
Recommended publications
  • Nebulette Is a Powerful Cytolinker Organizing Desmin and Actin in Mouse Hearts

    Nebulette Is a Powerful Cytolinker Organizing Desmin and Actin in Mouse Hearts

    M BoC | ARTICLE Nebulette is a powerful cytolinker organizing desmin and actin in mouse hearts Daniel A. Hernandeza,†, Christina M. Bennetta,†, Lyubov Dunina-Barkovskayaa, Tatjana Wedigb, Yassemi Capetanakic, Harald Herrmannb,d, and Gloria M. Conovera,* aDepartment of Biochemistry & Biophysics, Texas A&M University, College Station, TX 77843-3474; bDivision of Molecular Genetics, German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany; cCenter of Basic Research, Biomedi- cal Research Foundation Academy of Athens, Athens 11527, Greece; dInstitute of Neuropathology, University Hospital Erlangen, D-91054 Erlangen, Germany ABSTRACT In the hearts of patients bearing nebulette mutations, a severe general disorgani- Monitoring Editor zation in cardiomyocytes of the extrasarcomeric desmin intermediate filament system is fre- Robert D. Goldman quently observed. However, the molecular and functional relationship between the desmin Northwestern University cytoskeleton and nebulette-containing sarcomeres is still unclear. Here we report a high-affinity Received: Apr 18, 2016 in vitro interaction between nebulette and desmin filaments. A major interaction site has been Revised: Aug 31, 2016 mapped to the desmin α-helical rod domain, indicating that the filament core is directly in- Accepted: Oct 5, 2016 volved in the binding of nebulette. The disease-mutant desmin variants E245D and T453I ex- hibited increased binding affinity for nebulette, delayed filament assembly kinetics, and caused significant weakening of networks. In isolated chick cardiomyocytes and sections from canine heart, we revealed by ground-state depletion and confocal microscopies that module 5 of nebulette extends outward from Z-disk–associated desmin filaments toward the center of the sarcomere. Accordingly, in the myocardium of Des−/− mice, elevated levels of cardiac actin cor- related with alterations in the distribution of nebulette.
  • The Role of Z-Disc Proteins in Myopathy and Cardiomyopathy

    The Role of Z-Disc Proteins in Myopathy and Cardiomyopathy

    International Journal of Molecular Sciences Review The Role of Z-disc Proteins in Myopathy and Cardiomyopathy Kirsty Wadmore 1,†, Amar J. Azad 1,† and Katja Gehmlich 1,2,* 1 Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK; [email protected] (K.W.); [email protected] (A.J.A.) 2 Division of Cardiovascular Medicine, Radcliffe Department of Medicine and British Heart Foundation Centre of Research Excellence Oxford, University of Oxford, Oxford OX3 9DU, UK * Correspondence: [email protected]; Tel.: +44-121-414-8259 † These authors contributed equally. Abstract: The Z-disc acts as a protein-rich structure to tether thin filament in the contractile units, the sarcomeres, of striated muscle cells. Proteins found in the Z-disc are integral for maintaining the architecture of the sarcomere. They also enable it to function as a (bio-mechanical) signalling hub. Numerous proteins interact in the Z-disc to facilitate force transduction and intracellular signalling in both cardiac and skeletal muscle. This review will focus on six key Z-disc proteins: α-actinin 2, filamin C, myopalladin, myotilin, telethonin and Z-disc alternatively spliced PDZ-motif (ZASP), which have all been linked to myopathies and cardiomyopathies. We will summarise pathogenic variants identified in the six genes coding for these proteins and look at their involvement in myopathy and cardiomyopathy. Listing the Minor Allele Frequency (MAF) of these variants in the Genome Aggregation Database (GnomAD) version 3.1 will help to critically re-evaluate pathogenicity based on variant frequency in normal population cohorts.
  • List of Genes Associated with Sudden Cardiac Death (Scdgseta) Gene

    List of Genes Associated with Sudden Cardiac Death (Scdgseta) Gene

    List of genes associated with sudden cardiac death (SCDgseta) mRNA expression in normal human heart Entrez_I Gene symbol Gene name Uniprot ID Uniprot name fromb D GTEx BioGPS SAGE c d e ATP-binding cassette subfamily B ABCB1 P08183 MDR1_HUMAN 5243 √ √ member 1 ATP-binding cassette subfamily C ABCC9 O60706 ABCC9_HUMAN 10060 √ √ member 9 ACE Angiotensin I–converting enzyme P12821 ACE_HUMAN 1636 √ √ ACE2 Angiotensin I–converting enzyme 2 Q9BYF1 ACE2_HUMAN 59272 √ √ Acetylcholinesterase (Cartwright ACHE P22303 ACES_HUMAN 43 √ √ blood group) ACTC1 Actin, alpha, cardiac muscle 1 P68032 ACTC_HUMAN 70 √ √ ACTN2 Actinin alpha 2 P35609 ACTN2_HUMAN 88 √ √ √ ACTN4 Actinin alpha 4 O43707 ACTN4_HUMAN 81 √ √ √ ADRA2B Adrenoceptor alpha 2B P18089 ADA2B_HUMAN 151 √ √ AGT Angiotensinogen P01019 ANGT_HUMAN 183 √ √ √ AGTR1 Angiotensin II receptor type 1 P30556 AGTR1_HUMAN 185 √ √ AGTR2 Angiotensin II receptor type 2 P50052 AGTR2_HUMAN 186 √ √ AKAP9 A-kinase anchoring protein 9 Q99996 AKAP9_HUMAN 10142 √ √ √ ANK2/ANKB/ANKYRI Ankyrin 2 Q01484 ANK2_HUMAN 287 √ √ √ N B ANKRD1 Ankyrin repeat domain 1 Q15327 ANKR1_HUMAN 27063 √ √ √ ANKRD9 Ankyrin repeat domain 9 Q96BM1 ANKR9_HUMAN 122416 √ √ ARHGAP24 Rho GTPase–activating protein 24 Q8N264 RHG24_HUMAN 83478 √ √ ATPase Na+/K+–transporting ATP1B1 P05026 AT1B1_HUMAN 481 √ √ √ subunit beta 1 ATPase sarcoplasmic/endoplasmic ATP2A2 P16615 AT2A2_HUMAN 488 √ √ √ reticulum Ca2+ transporting 2 AZIN1 Antizyme inhibitor 1 O14977 AZIN1_HUMAN 51582 √ √ √ UDP-GlcNAc: betaGal B3GNT7 beta-1,3-N-acetylglucosaminyltransfe Q8NFL0
  • Supporting Information

    Supporting Information

    Supporting Information Figure S1. The functionality of the tagged Arp6 and Swr1 was confirmed by monitoring cell growth and sensitivity to hydeoxyurea (HU). Five-fold serial dilutions of each strain were plated on YPD with or without 50 mM HU and incubated at 30°C or 37°C for 3 days. Figure S2. Localization of Arp6 and Swr1 on chromosome 3. The binding of Arp6-FLAG (top), Swr1-FLAG (middle), and Arp6-FLAG in swr1 cells (bottom) are compared. The position of Tel 3L, Tel 3R, CEN3, and the RP gene are shown under the panels. Figure S3. Localization of Arp6 and Swr1 on chromosome 4. The binding of Arp6-FLAG (top), Swr1-FLAG (middle), and Arp6-FLAG in swr1 cells (bottom) in the whole chromosome region are compared. The position of Tel 4L, Tel 4R, CEN4, SWR1, and RP genes are shown under the panels. Figure S4. Localization of Arp6 and Swr1 on the region including the SWR1 gene of chromosome 4. The binding of Arp6- FLAG (top), Swr1-FLAG (middle), and Arp6-FLAG in swr1 cells (bottom) are compared. The position and orientation of the SWR1 gene is shown. Figure S5. Localization of Arp6 and Swr1 on chromosome 5. The binding of Arp6-FLAG (top), Swr1-FLAG (middle), and Arp6-FLAG in swr1 cells (bottom) are compared. The position of Tel 5L, Tel 5R, CEN5, and the RP genes are shown under the panels. Figure S6. Preferential localization of Arp6 and Swr1 in the 5′ end of genes. Vertical bars represent the binding ratio of proteins in each locus.
  • Identification of Small Molecule Modulators of Diguanylate Cyclase

    Identification of Small Molecule Modulators of Diguanylate Cyclase

    bioRxiv preprint doi: https://doi.org/10.1101/402909; this version posted August 28, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Identification of Small Molecule Modulators of Diguanylate Cyclase by FRET-based High-Throughput-Screening Matthias Christen1, , Cassandra Kamischke2, Hemantha D. Kulasekara2, Kathleen C. Olivas3, Bridget R. Kulasekara4, Beat Christen1, Toni Kline5, and Samuel I. Miller2,4,6, 1Institute of Molecular Systems Biology, Eidgenössische Technische Hochschule (ETH) Zürich, CH-8093 Zürich, Switzerland 2Department of Microbiology, University of Washington, Seattle, United States 3Seattle Genetics, Inc., 21823 30th Drive SE, Bothell, Washington 98021 4Department of Genome Sciences, University of Washington, Seattle 5Sutro Biopharma, 310 Utah Avenue, South San Francisco, CA 94080 6Department of Medicine, University of Washington, Seattle The bacterial second messenger cyclic diguanosine monophos- parent role of c-di-GMP in the cell cycle and the presence of phate (c-di-GMP) is a key regulator of cellular motility, the cell many paralogous DGC enzymes controlling diverse cellular cycle, and biofilm formation with its resultant antibiotic tol- functions indicate that there is likely tight spatial and tem- erance, which may make chronic infections difficult to treat. poral regulation of c-di-GMP (10–12). Bacterial genomes Therefore, diguanylate cyclases, which regulate the spatiotem- encode multiple GGDEF domains in proteins with signal- poral production of c-di-GMP, may be attractive drug tar- sensing domains (13).
  • Atherosclerosis-Susceptible and Atherosclerosis-Resistant Pigeon Aortic Cells Express Different Genes in Vivo

    Atherosclerosis-Susceptible and Atherosclerosis-Resistant Pigeon Aortic Cells Express Different Genes in Vivo

    University of New Hampshire University of New Hampshire Scholars' Repository New Hampshire Agricultural Experiment Station Publications New Hampshire Agricultural Experiment Station 7-1-2013 Atherosclerosis-susceptible and atherosclerosis-resistant pigeon aortic cells express different genes in vivo Janet L. Anderson University of New Hampshire, [email protected] C. M. Ashwell University of New Hampshire - Main Campus S. C. Smith University of New Hampshire - Main Campus R. Shine University of New Hampshire - Main Campus E. C. Smith University of New Hampshire - Main Campus See next page for additional authors Follow this and additional works at: https://scholars.unh.edu/nhaes Part of the Poultry or Avian Science Commons Recommended Citation J. L. Anderson, C. M. Ashwell, S. C. Smith, R. Shine, E. C. Smith and R. L. Taylor, Jr. Atherosclerosis- susceptible and atherosclerosis-resistant pigeon aortic cells express different genes in vivo Poultry Science (2013) 92 (10): 2668-2680 doi:10.3382/ps.2013-03306 This Article is brought to you for free and open access by the New Hampshire Agricultural Experiment Station at University of New Hampshire Scholars' Repository. It has been accepted for inclusion in New Hampshire Agricultural Experiment Station Publications by an authorized administrator of University of New Hampshire Scholars' Repository. For more information, please contact [email protected]. Authors Janet L. Anderson, C. M. Ashwell, S. C. Smith, R. Shine, E. C. Smith, and Robert L. Taylor Jr. This article is available at University of New Hampshire Scholars' Repository: https://scholars.unh.edu/nhaes/207 Atherosclerosis-susceptible and atherosclerosis-resistant pigeon aortic cells express different genes in vivo J.
  • (1,3)-Β-D-Glucan Synthase Gene Family in Hordeum Vulgare

    (1,3)-Β-D-Glucan Synthase Gene Family in Hordeum Vulgare

    lJ Ítìr¡ 1 t¡ The Putative ( 1,3)-9-l-Glucan Synthase Gene Family in Hordeum vulgare Submitted by Michael Scott Schober This thesis is submitted in fulfilment of the requirements for the degree of Doctor of Philosophy Discipline of Plant and Pest Science School of Agriculture and Wine Faculty of Sciences University of Adelaide,'Waite Campus Glen Osmond, South Australia, 5064, Australia January,2006 Statement of Authorship This thesis contains no material that has been accepted for the award of any other degree or diploma in any university and that, to the best of my knowledge and belief, this thesis contains no material previously published or written by another person, except where due reference being made in the text of the thesis. I give consent to this copy of my thesis, when deposited in the University Libraries, being available for photocopying and loan. Michael Scott Schober January 2006 ll Table of Contents STATEMENT or AutgonsulP ll TABLE OF CONTENTS iii ACKNOWLEDGEMENTS vi PUBLTCATIONS vii ABBREVIATIONS viii ABSTRACT ix CHAPTER 1 General Introduction I 1.I INTRODUCTION 2 1.2 (1,3)-p-D-GLUCAN 4 1.2.1 StructuralProperties 4 1.2.2 Cellular Locations and Associated Functions 6 1.2.2.1 Cell Plate Formation 6 1,2.2.2 Plasmodesmata and Sieve Plate Pores 7 1.2.2.3 ReproductiveTissues 9 1.3 STRESSRELATED(1,3)-B-o-GLUCANDEPOSITION ll I .3. 1 Abiotic stress ll l.3.l.l Wounding ll 1.3.1.2 Metaltoxicity t2 1.3.2 Blotic Stress 12 1.3.2.1 Viral infection t2 1.3.2.2 Bacterialinfection 13 1.3.2.3 Nematode infection l3 1.3.2.4 Fungal Infection
  • Addressing 360O of Biochemical Imbalances to Restore Balance and Relieve Symptoms

    Addressing 360O of Biochemical Imbalances to Restore Balance and Relieve Symptoms

    Addressing 360o of biochemical imbalances to restore balance and relieve symptoms. Product Guide Effective June 2015 Product availability subject to change without notice. View the most current catalog electronically at www.neuroscienceinc.com/productcatalog Dr. Gottfried Kellermann and Mieke Kellermann Ushering in a New Age of Personalized Care As NeuroScience, Inc. enters its 15th year in business, we reflect on the driving force behind our services- providing you, the practitioner, with tools that allow you to more efficiently and effectively care for your patients. Together with our laboratory partner, Pharmasan Labs, Inc. we pioneered the Assess and Address™ approach for personalized patient care. New and Exciting Direction We recognize the evolving changes in patient care and patient expectation from their healthcare practitioners. More than ever, patients are taking control of their health and demanding care that allows them to get better faster and enjoy the healthy lifestyle they deserve. NeuroScience, along with Pharmasan Labs, has taken the lead in focusing on a model that not only identifies the imbalances behind many symptoms but how the network of those imbalances indicates deeper issues. This network approach points you in the direction of the root cause of patient symptoms, which when resolved can lead to improved, long-term health outcomes. Never satisfied with the status quo, we will continue to innovate to provide you with unparalleled support toward this end. A Provider of Personalized, Clinical Solutions…this is WHO WE ARE. Together, NeuroScience and Pharmasan are committed to providing you with the clinical assessments and tools you need to thrive in this rapidly changing healthcare market while better serving your patients.
  • Snapshot: Actin Regulators II Anosha D

    Snapshot: Actin Regulators II Anosha D

    SnapShot: Actin Regulators II Anosha D. Siripala and Matthew D. Welch Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA Representative Proteins Protein Family H. sapiens D. melanogaster C. elegans A. thaliana S. cerevisiae Endocytosis and Exocytosis ABP1/drebrin mABP1, drebrin, drebrin- †Q95RN0 †Q9XUT0 Abp1 like EPS15 EPS15 Eps-15 EHS-1 †Q56WL2 Pan1 HIP1R HIP1R †Q8MQK1 †O62142 Sla2 Synapsin synapsin Ia, Ib, IIa, IIb, III Synapsin SNN-1 Plasma Membrane Association Anillin anillin Scraps ANI-1, 2, 3 Annexins annexin A1–11, 13 (actin Annexin B9-11 NEX-1–4 ANN1-8 binding: 1, 2, 6) ERM proteins ezrin, radixin, moesin DMoesin ERM-1 MARCKS MARCKS, MRP/ Akap200 MACMARCKS/F52 Merlin *merlin/NF2 Merlin NFM-1 Protein 4.1 4.1R, G, N, B Coracle Spectrin α-spectrin (1–2), β-spectrin α-spectrin, β-spectrin, β heavy- SPC-1 (α-spectrin), UNC-70 (1–4), β heavy-spectrin/ spectrin/Karst (β-spectrin), SMA-1 (β heavy- karst spectrin) Identifi ed Cellular Role: X Membrane traffi cking and phagocytosis Cell-Cell Junctions X Cytokinesis α-catenin α-catenin 1–3 α-catenin HMP-1 X Cell surface organization and dynamics X Cell adhesion Afadin afadin/AF6 Canoe AFD-1 X Multiple functions ZO-1 ZO-1, ZO-2, ZO-3 ZO-1/Polychaetoid †Q56VX4 X Other/unknown Cell-Extracellular Matrix Junctions †UNIPROT database accession number *Mutation linked to human disease Dystrophin/utrophin *dystrophin, utrophin/ Dystrophin DYS-1 DRP1, DRP2 LASP LASP-1, LASP-2, LIM- Lasp †P34416 nebulette Palladin palladin Parvin α-, β-, χ-parvin †Q9VWD0 PAT-6
  • Brigitte M. Jockusch Editor the Actin Cytoskeleton Handbook of Experimental Pharmacology

    Brigitte M. Jockusch Editor the Actin Cytoskeleton Handbook of Experimental Pharmacology

    Handbook of Experimental Pharmacology 235 Brigitte M. Jockusch Editor The Actin Cytoskeleton Handbook of Experimental Pharmacology Volume 235 Editor-in-Chief James E. Barrett, Philadelphia Editorial Board V. Flockerzi, Homburg M.A. Frohman, Stony Brook, NY P. Geppetti, Florence F.B. Hofmann, Mu¨nchen M.C. Michel, Mainz C.P. Page, London W. Rosenthal, Berlin K. Wang, Beijing More information about this series at http://www.springer.com/series/164 Brigitte M. Jockusch Editor The Actin Cytoskeleton Editor Brigitte M. Jockusch Cell Biology, Life Sciences BRICS, TU Braunschweig Braunschweig, Germany ISSN 0171-2004 ISSN 1865-0325 (electronic) Handbook of Experimental Pharmacology ISBN 978-3-319-46369-8 ISBN 978-3-319-46371-1 (eBook) DOI 10.1007/978-3-319-46371-1 Library of Congress Control Number: 2016963070 # Springer International Publishing AG 2017 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication.
  • Proteasomes: Unfoldase-Assisted Protein Degradation Machines

    Proteasomes: Unfoldase-Assisted Protein Degradation Machines

    Biol. Chem. 2020; 401(1): 183–199 Review Parijat Majumder and Wolfgang Baumeister* Proteasomes: unfoldase-assisted protein degradation machines https://doi.org/10.1515/hsz-2019-0344 housekeeping functions such as cell cycle control, signal Received August 13, 2019; accepted October 2, 2019; previously transduction, transcription, DNA repair and translation published online October 29, 2019 (Alves dos Santos et al., 2001; Goldberg, 2007; Bader and Steller, 2009; Koepp, 2014). Consequently, any disrup- Abstract: Proteasomes are the principal molecular tion of selective protein degradation pathways leads to a machines for the regulated degradation of intracellular broad array of pathological states, including cancer, neu- proteins. These self-compartmentalized macromolecu- rodegeneration, immune-related disorders, cardiomyo- lar assemblies selectively degrade misfolded, mistrans- pathies, liver and gastrointestinal disorders, and ageing lated, damaged or otherwise unwanted proteins, and (Dahlmann, 2007; Motegi et al., 2009; Dantuma and Bott, play a pivotal role in the maintenance of cellular proteo- 2014; Schmidt and Finley, 2014). stasis, in stress response, and numerous other processes In eukaryotes, two major pathways have been identi- of vital importance. Whereas the molecular architecture fied for the selective removal of unwanted proteins – the of the proteasome core particle (CP) is universally con- ubiquitin-proteasome-system (UPS), and the autophagy- served, the unfoldase modules vary in overall structure, lysosome pathway (Ciechanover, 2005; Dikic, 2017). UPS subunit complexity, and regulatory principles. Proteas- constitutes the principal degradation route for intracel- omal unfoldases are AAA+ ATPases (ATPases associated lular proteins, whereas cellular organelles, cell-surface with a variety of cellular activities) that unfold protein proteins, and invading pathogens are mostly degraded substrates, and translocate them into the CP for degra- via autophagy.
  • Human Induced Pluripotent Stem Cell–Derived Podocytes Mature Into Vascularized Glomeruli Upon Experimental Transplantation

    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