Epileptic Encephalopathy-Causing Mutations in DNM1 Impair Synaptic Vesicle Endocytosis
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Dynamin Functions and Ligands: Classical Mechanisms Behind
1521-0111/91/2/123–134$25.00 http://dx.doi.org/10.1124/mol.116.105064 MOLECULAR PHARMACOLOGY Mol Pharmacol 91:123–134, February 2017 Copyright ª 2017 by The American Society for Pharmacology and Experimental Therapeutics MINIREVIEW Dynamin Functions and Ligands: Classical Mechanisms Behind Mahaveer Singh, Hemant R. Jadhav, and Tanya Bhatt Department of Pharmacy, Birla Institute of Technology and Sciences Pilani, Pilani Campus, Rajasthan, India Received May 5, 2016; accepted November 17, 2016 Downloaded from ABSTRACT Dynamin is a GTPase that plays a vital role in clathrin-dependent pathophysiology of various disorders, such as Alzheimer’s disease, endocytosis and other vesicular trafficking processes by acting Parkinson’s disease, Huntington’s disease, Charcot-Marie-Tooth as a pair of molecular scissors for newly formed vesicles originating disease, heart failure, schizophrenia, epilepsy, cancer, dominant ’ from the plasma membrane. Dynamins and related proteins are optic atrophy, osteoporosis, and Down s syndrome. This review is molpharm.aspetjournals.org important components for the cleavage of clathrin-coated vesicles, an attempt to illustrate the dynamin-related mechanisms involved phagosomes, and mitochondria. These proteins help in organelle in the above-mentioned disorders and to help medicinal chemists division, viral resistance, and mitochondrial fusion/fission. Dys- to design novel dynamin ligands, which could be useful in the function and mutations in dynamin have been implicated in the treatment of dynamin-related disorders. Introduction GTP hydrolysis–dependent conformational change of GTPase dynamin assists in membrane fission, leading to the generation Dynamins were originally discovered in the brain and identi- of endocytic vesicles (Praefcke and McMahon, 2004; Ferguson at ASPET Journals on September 23, 2021 fied as microtubule binding partners. -
Conserved and Novel Properties of Clathrin-Mediated Endocytosis in Dictyostelium Discoideum" (2012)
Rockefeller University Digital Commons @ RU Student Theses and Dissertations 2012 Conserved and Novel Properties of Clathrin- Mediated Endocytosis in Dictyostelium Discoideum Laura Macro Follow this and additional works at: http://digitalcommons.rockefeller.edu/ student_theses_and_dissertations Part of the Life Sciences Commons Recommended Citation Macro, Laura, "Conserved and Novel Properties of Clathrin-Mediated Endocytosis in Dictyostelium Discoideum" (2012). Student Theses and Dissertations. Paper 163. This Thesis is brought to you for free and open access by Digital Commons @ RU. It has been accepted for inclusion in Student Theses and Dissertations by an authorized administrator of Digital Commons @ RU. For more information, please contact [email protected]. CONSERVED AND NOVEL PROPERTIES OF CLATHRIN- MEDIATED ENDOCYTOSIS IN DICTYOSTELIUM DISCOIDEUM A Thesis Presented to the Faculty of The Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy by Laura Macro June 2012 © Copyright by Laura Macro 2012 CONSERVED AND NOVEL PROPERTIES OF CLATHRIN- MEDIATED ENDOCYTOSIS IN DICTYOSTELIUM DISCOIDEUM Laura Macro, Ph.D. The Rockefeller University 2012 The protein clathrin mediates one of the major pathways of endocytosis from the extracellular milieu and plasma membrane. Clathrin functions with a network of interacting accessory proteins, one of which is the adaptor complex AP-2, to co-ordinate vesicle formation. Disruption of genes involved in clathrin-mediated endocytosis causes embryonic lethality in multicellular animals suggesting that clathrin-mediated endocytosis is a fundamental cellular process. However, loss of clathrin-mediated endocytosis genes in single cell eukaryotes, such as S.cerevisiae (yeast), does not cause lethality, suggesting that clathrin may convey specific advantages for multicellularity. -
Investigation of the Underlying Hub Genes and Molexular Pathogensis in Gastric Cancer by Integrated Bioinformatic Analyses
bioRxiv preprint doi: https://doi.org/10.1101/2020.12.20.423656; this version posted December 22, 2020. 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. Investigation of the underlying hub genes and molexular pathogensis in gastric cancer by integrated bioinformatic analyses Basavaraj Vastrad1, Chanabasayya Vastrad*2 1. Department of Biochemistry, Basaveshwar College of Pharmacy, Gadag, Karnataka 582103, India. 2. Biostatistics and Bioinformatics, Chanabasava Nilaya, Bharthinagar, Dharwad 580001, Karanataka, India. * Chanabasayya Vastrad [email protected] Ph: +919480073398 Chanabasava Nilaya, Bharthinagar, Dharwad 580001 , Karanataka, India bioRxiv preprint doi: https://doi.org/10.1101/2020.12.20.423656; this version posted December 22, 2020. 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. Abstract The high mortality rate of gastric cancer (GC) is in part due to the absence of initial disclosure of its biomarkers. The recognition of important genes associated in GC is therefore recommended to advance clinical prognosis, diagnosis and and treatment outcomes. The current investigation used the microarray dataset GSE113255 RNA seq data from the Gene Expression Omnibus database to diagnose differentially expressed genes (DEGs). Pathway and gene ontology enrichment analyses were performed, and a proteinprotein interaction network, modules, target genes - miRNA regulatory network and target genes - TF regulatory network were constructed and analyzed. Finally, validation of hub genes was performed. The 1008 DEGs identified consisted of 505 up regulated genes and 503 down regulated genes. -
Supplementary Material
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) J Neurol Neurosurg Psychiatry Page 1 / 45 SUPPLEMENTARY MATERIAL Appendix A1: Neuropsychological protocol. Appendix A2: Description of the four cases at the transitional stage. Table A1: Clinical status and center proportion in each batch. Table A2: Complete output from EdgeR. Table A3: List of the putative target genes. Table A4: Complete output from DIANA-miRPath v.3. Table A5: Comparison of studies investigating miRNAs from brain samples. Figure A1: Stratified nested cross-validation. Figure A2: Expression heatmap of miRNA signature. Figure A3: Bootstrapped ROC AUC scores. Figure A4: ROC AUC scores with 100 different fold splits. Figure A5: Presymptomatic subjects probability scores. Figure A6: Heatmap of the level of enrichment in KEGG pathways. Kmetzsch V, et al. J Neurol Neurosurg Psychiatry 2021; 92:485–493. doi: 10.1136/jnnp-2020-324647 BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) J Neurol Neurosurg Psychiatry Appendix A1. Neuropsychological protocol The PREV-DEMALS cognitive evaluation included standardized neuropsychological tests to investigate all cognitive domains, and in particular frontal lobe functions. The scores were provided previously (Bertrand et al., 2018). Briefly, global cognitive efficiency was evaluated by means of Mini-Mental State Examination (MMSE) and Mattis Dementia Rating Scale (MDRS). Frontal executive functions were assessed with Frontal Assessment Battery (FAB), forward and backward digit spans, Trail Making Test part A and B (TMT-A and TMT-B), Wisconsin Card Sorting Test (WCST), and Symbol-Digit Modalities test. -
Identification of Potential Key Genes and Pathway Linked with Sporadic Creutzfeldt-Jakob Disease Based on Integrated Bioinformatics Analyses
medRxiv preprint doi: https://doi.org/10.1101/2020.12.21.20248688; this version posted December 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. Identification of potential key genes and pathway linked with sporadic Creutzfeldt-Jakob disease based on integrated bioinformatics analyses Basavaraj Vastrad1, Chanabasayya Vastrad*2 , Iranna Kotturshetti 1. Department of Biochemistry, Basaveshwar College of Pharmacy, Gadag, Karnataka 582103, India. 2. Biostatistics and Bioinformatics, Chanabasava Nilaya, Bharthinagar, Dharwad 580001, Karanataka, India. 3. Department of Ayurveda, Rajiv Gandhi Education Society`s Ayurvedic Medical College, Ron, Karnataka 562209, India. * Chanabasayya Vastrad [email protected] Ph: +919480073398 Chanabasava Nilaya, Bharthinagar, Dharwad 580001 , Karanataka, India NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. medRxiv preprint doi: https://doi.org/10.1101/2020.12.21.20248688; this version posted December 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. Abstract Sporadic Creutzfeldt-Jakob disease (sCJD) is neurodegenerative disease also called prion disease linked with poor prognosis. The aim of the current study was to illuminate the underlying molecular mechanisms of sCJD. The mRNA microarray dataset GSE124571 was downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were screened. -
Epileptic Mechanisms Shared by Alzheimer's Disease
International Journal of Molecular Sciences Review Epileptic Mechanisms Shared by Alzheimer’s Disease: Viewed via the Unique Lens of Genetic Epilepsy Jing-Qiong Kang 1,2 1 Department of Neurology & Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232-8552, USA; [email protected]; Tel.: +1-615-936-8399; Fax: +1-615-322-5517 2 Vanderbilt Kennedy Center of Human Development, Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37232-8522, USA Abstract: Our recent work on genetic epilepsy (GE) has identified common mechanisms between GE and neurodegenerative diseases including Alzheimer’s disease (AD). Although both disorders are seemingly unrelated and occur at opposite ends of the age spectrum, it is likely there are shared mechanisms and studies on GE could provide unique insights into AD pathogenesis. Neurodegen- erative diseases are typically late-onset disorders, but the underlying pathology may have already occurred long before the clinical symptoms emerge. Pathophysiology in the early phase of these diseases is understudied but critical for developing mechanism-based treatment. In AD, increased seizure susceptibility and silent epileptiform activity due to disrupted excitatory/inhibitory (E/I) balance has been identified much earlier than cognition deficit. Increased epileptiform activity is likely a main pathology in the early phase that directly contributes to impaired cognition. It is an enormous challenge to model the early phase of pathology with conventional AD mouse models due to the chronic disease course, let alone the complex interplay between subclinical nonconvulsive epileptiform activity, AD pathology, and cognition deficit. We have extensively studied GE, especially with gene mutations that affect the GABA pathway such as mutations in GABAA receptors and GABA transporter Citation: Kang, J.-Q. -
Integrating Protein Copy Numbers with Interaction Networks to Quantify Stoichiometry in Mammalian Endocytosis
bioRxiv preprint doi: https://doi.org/10.1101/2020.10.29.361196; this version posted October 29, 2020. 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-ND 4.0 International license. Integrating protein copy numbers with interaction networks to quantify stoichiometry in mammalian endocytosis Daisy Duan1, Meretta Hanson1, David O. Holland2, Margaret E Johnson1* 1TC Jenkins Department of Biophysics, Johns Hopkins University, 3400 N Charles St, Baltimore, MD 21218. 2NIH, Bethesda, MD, 20892. *Corresponding Author: [email protected] bioRxiv preprint doi: https://doi.org/10.1101/2020.10.29.361196; this version posted October 29, 2020. 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-ND 4.0 International license. Abstract Proteins that drive processes like clathrin-mediated endocytosis (CME) are expressed at various copy numbers within a cell, from hundreds (e.g. auxilin) to millions (e.g. clathrin). Between cell types with identical genomes, copy numbers further vary significantly both in absolute and relative abundance. These variations contain essential information about each protein’s function, but how significant are these variations and how can they be quantified to infer useful functional behavior? Here, we address this by quantifying the stoichiometry of proteins involved in the CME network. We find robust trends across three cell types in proteins that are sub- vs super-stoichiometric in terms of protein function, network topology (e.g. -
A Centronuclear Myopathy-Dynamin 2 Mutation Impairs Skeletal Muscle Structure and Function in Mice
Human Molecular Genetics, 2010, Vol. 19, No. 24 4820–4836 doi:10.1093/hmg/ddq413 Advance Access published on September 21, 2010 A centronuclear myopathy-dynamin 2 mutation impairs skeletal muscle structure and function in mice Anne-Ce´cile Durieux1,2,3,4, Alban Vignaud1,2,3,4, Bernard Prudhon1,2,3,4, Mai Thao Viou1,2,3,4, Maud Beuvin1,2,3,4, Ste´phane Vassilopoulos1,2,3,4, Bodvae¨l Fraysse1,2,3,4, Arnaud Ferry1,2,3,4, ∗ Jeanne Laine´ 1,2,3,4, Norma B. Romero 1,2,3,4,5, Pascale Guicheney1,6 and Marc Bitoun1,2,3,4, Downloaded from https://academic.oup.com/hmg/article/19/24/4820/680275 by guest on 25 September 2021 1Universite´ Pierre et Marie Curie-Paris 6, IFR14, Paris F-75013, France, 2CNRS, UMR 7215, Paris, France, 3Inserm, U974, Paris F-75013, France, 4Institut de Myologie, Paris, France, 5AP-HP, Groupe Hospitalier Pitie´-Salpeˆtrie`re, Paris F-75013, France and 6Inserm, U956, Paris F-75013, France Received July 1, 2010; Revised and Accepted September 16, 2010 Autosomal dominant centronuclear myopathy (AD-CNM) is due to mutations in the gene encoding dynamin 2 (DNM2) involved in endocytosis and intracellular membrane trafficking. To understand the pathomechanisms resulting from a DNM2 mutation, we generated a knock-in mouse model expressing the most frequent AD- CNM mutation (KI-Dnm2R465W). Heterozygous (HTZ) mice developed a myopathy showing a specific spatial and temporal muscle involvement. In the primarily and prominently affected tibialis anterior muscle, impair- ment of the contractile properties was evidenced at weaning and was progressively associated with atrophy and histopathological abnormalities mainly affecting mitochondria and reticular network. -
NOTCH-Induced Rerouting of Endosomal Trafficking Disables Regulatory T Cells in Vasculitis
NOTCH-induced rerouting of endosomal trafficking disables regulatory T cells in vasculitis Ke Jin, … , Jorg J. Goronzy, Cornelia M. Weyand J Clin Invest. 2021;131(1):e136042. https://doi.org/10.1172/JCI136042. Research Article Autoimmunity Immunology Graphical abstract Find the latest version: https://jci.me/136042/pdf The Journal of Clinical Investigation RESEARCH ARTICLE NOTCH-induced rerouting of endosomal trafficking disables regulatory T cells in vasculitis Ke Jin,1 Zhenke Wen,1 Bowen Wu,1 Hui Zhang,1 Jingtao Qiu,1 Yanan Wang,1 Kenneth J. Warrington,2 Gerald J. Berry,3 Jorg J. Goronzy,1 and Cornelia M. Weyand1 1Department of Medicine, Stanford University School of Medicine, Stanford, California, USA. 2Department of Medicine, Mayo Alix School of Medicine, Rochester, Minnesota, USA. 3Department of Pathology, Stanford University School of Medicine, Stanford, California, USA. The aorta and the large conductive arteries are immunoprivileged tissues and are protected against inflammatory attack. A breakdown of immunoprivilege leads to autoimmune vasculitis, such as giant cell arteritis, in which CD8+ Treg cells fail to contain CD4+ T cells and macrophages, resulting in the formation of tissue-destructive granulomatous lesions. Here, we report that the molecular defect of malfunctioning CD8+ Treg cells lies in aberrant NOTCH4 signaling that deviates endosomal trafficking and minimizes exosome production. By transcriptionally controlling the profile of RAB GTPases, NOTCH4 signaling restricted vesicular secretion of the enzyme NADPH oxidase 2 (NOX2). Specifically, NOTCH4hiCD8+ Treg cells increased RAB5A and RAB11A expression and suppressed RAB7A, culminating in the accumulation of early and recycling endosomes and sequestering of NOX2 in an intracellular compartment. RAB7AloCD8+ Treg cells failed in the surface translocation and exosomal release of NOX2. -
Defining the Dynamin-Based Ring Organizing Center on The
© 2017. Published by The Company of Biologists Ltd | Journal of Cell Science (2017) 130, 853-867 doi:10.1242/jcs.199182 RESEARCH ARTICLE Defining the dynamin-based ring organizing center on the peroxisome-dividing machinery isolated from Cyanidioschyzon merolae Yuuta Imoto1, Yuichi Abe1, Kanji Okumoto2, Masanori Honsho1, Haruko Kuroiwa3,4, Tsuneyoshi Kuroiwa3,4 and Yukio Fujiki1,* ABSTRACT elastic stress and requires external force to accomplish it. Numerous Organelle division is executed through contraction of a ring-shaped molecular genetic studies have thus determined fission factors – supramolecular dividing machinery. A core component of the involved in the fission process of many membranes these include machinery is the dynamin-based ring conserved during the division a member of the GTPase dynamin family in the division of of mitochondrion, plastid and peroxisome. Here, using isolated mitochondrion, plastid and peroxisome (Bleazard et al., 1999; peroxisome-dividing (POD) machinery from a unicellular red algae, Miyagishima et al., 2003; Koch et al., 2003) and in synaptic vesicle Cyanidioschyzon merolae, we identified a dynamin-based ring endocytosis (Obar et al., 1999; Chen et al., 1991; van der Bliek organizing center (DOC) that acts as an initiation point for formation and Meyerowrtz, 1991). Despite their biological importance, of the dynamin-based ring. C. merolae contains a single peroxisome, the ultrastructure and molecular mechanism of supramolecular the division of which can be highly synchronized by light–dark division machinery remain enigmatic because isolation and direct in vivo stimulation; thus, intact POD machinery can be isolated in bulk. observation of the machinery is difficult as most of the model Dynamin-based ring homeostasis is maintained by the turnover of the organism contains numerous organelles and vesicles that are shaped GTP-bound form of the dynamin-related protein Dnm1 between the irregularly and divide randomly. -
Association Between SNAP25 and Human Glioblastoma Multiform: a Comprehensive Bioinformatic Analysis
Bioscience Reports (2020) 40 BSR20200516 https://doi.org/10.1042/BSR20200516 Research Article Association between SNAP25 and human glioblastoma multiform: a comprehensive bioinformatic analysis Cheng Yu*, Jianxing Yin*, Xiefeng Wang*, Lijiu Chen, Yutian Wei, Chenfei Lu and Yongping You Downloaded from http://portlandpress.com/bioscirep/article-pdf/40/6/BSR20200516/883642/bsr-2020-0516.pdf by guest on 27 September 2021 Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China Correspondence: Yongping You ([email protected]) Background: Glioblastoma multiforme (GBM) is a most common aggressive malignant brain tumor. In recent years, targeted therapy has been increasingly applied in GBM treatment. Methods: In the present study, GSE22866 was downloaded from gene expression omnibus (GEO). The genomic and clinical data were obtained from TCGA. The differentially expressed genes (DEGs) were identified and functional analysis was performed using clusterprofiler. Then, the co-expression network for the DEGs was established using the “WGCNA” pack- age. Next, the protein–protein interaction (PPI) was assessed using Search Tool for the Retrieval of Interacting Genes Database (STRING) and hub modules in Cytoscape were screened. The Venn diagram was plotted to showcase the overlapped hub DEGs in PPI net- work and TCGA. Univariate and multivariate Cox proportional hazards regression analyses were performed to predict the risk score of each patient. Validations of the hub gene were completed in other databases. Results: Functional analysis of the DEGs verified the involvement of DEGs in growth fac- tor binding and gated channel activity. Among the 10 GBM-related modules, the red one displayed the strongest tie with GBM. -
DNM1 Encephalopathy a New Disease of Vesicle Fission
Published Ahead of Print on June 30, 2017 as 10.1212/WNL.0000000000004152 DNM1 encephalopathy A new disease of vesicle fission Sarah von Spiczak, MD* ABSTRACT * Katherine L. Helbig, MS Objective: To evaluate the phenotypic spectrum caused by mutations in dynamin 1 (DNM1), Deepali N. Shinde, PhD encoding the presynaptic protein DNM1, and to investigate possible genotype-phenotype corre- Robert Huether, PhD lations and predicted functional consequences based on structural modeling. Manuela Pendziwiat, Methods: We reviewed phenotypic data of 21 patients (7 previously published) with DNM1 mu- Dipl-Biol tations. We compared mutation data to known functional data and undertook biomolecular mod- Charles Lourenço, MD, eling to assess the effect of the mutations on protein function. PhD DNM1 Mark E. Nunes, MD Results: We identified 19 patients with de novo mutations in and a sibling pair who had an Dean P. Sarco, MD inherited mutation from a mosaic parent. Seven patients (33.3%) carried the recurrent Richard A. Kaplan, MD p.Arg237Trp mutation. A common phenotype emerged that included severe to profound intel- Dennis J. Dlugos, MD lectual disability and muscular hypotonia in all patients and an epilepsy characterized by infantile Heidi Kirsch, MD spasms in 16 of 21 patients, frequently evolving into Lennox-Gastaut syndrome. Two patients Anne Slavotinek, MD had profound global developmental delay without seizures. In addition, we describe a single Maria R. Cilio, MD, PhD patient with normal development before the onset of a catastrophic epilepsy, consistent with Mackenzie C. Cervenka, febrile infection-related epilepsy syndrome at 4 years. All mutations cluster within the GTPase or MD middle domains, and structural modeling and existing functional data suggest a dominant- Julie S.