Mutant UBQLN2 Promotes Toxicity by Modulating Intrinsic Self-Assembly
Total Page:16
File Type:pdf, Size:1020Kb
Load more
Recommended publications
-
Structural Studies of C9orf72-SMCR8-WDR41 Protein Complex
Structural Studies of C9orf72-SMCR8-WDR41 Protein Complex Valeria Shkuratova Department of Biochemistry McGill University, Montreal A thesis submitted to McGill University in partial fulfillment of the requirements of the degree of Master of Science © Valeria Shkuratova, 2020 Table of Contents Abstract ............................................................................................................................................ 3 Résumé ............................................................................................................................................ 4 Acknowledgment ............................................................................................................................. 5 Author Contribution ........................................................................................................................ 6 List of Abbreviations ....................................................................................................................... 7 List of Figures .................................................................................................................................. 9 List of Tables ................................................................................................................................... 9 Introduction ................................................................................................................................... 10 1. Amyotrophic Lateral Sclerosis (ALS) .............................................................................. -
The Proline/Arginine Dipeptide from Hexanucleotide Repeat Expanded C9ORF72 Inhibits the Proteasome
New Research Disorders of the Nervous System The Proline/Arginine Dipeptide from Hexanucleotide Repeat Expanded C9ORF72 Inhibits the Proteasome Jelena Mojsilovic-Petrovic,4 Won Hoon Choi,5 Nathaniel Safren,6 ء,Matthews Lan,3 ء,Rahul Gupta,1,2 Sami Barmada,6 Min Jae Lee,5 and Robert Kalb4,7 DOI:http://dx.doi.org/10.1523/ENEURO.0249-16.2017 1Department of Chemical and Biomolecular Engineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA, 19104, 2Department of Biology, College of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, 19104, 3Department of Biochemistry, College of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, 19104, 4Division of Neurology, Department of Pediatrics, Research Institute, Children’s Hospital of Philadelphia, Philadelphia, PA, 19104, 5Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea, 6Department of Neurology, University of Michigan, Ann Arbor, MI, 48109, and 7Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104 Abstract An intronic hexanucleotide repeat expansion (HRE) mutation in the C9ORF72 gene is the most common cause of familial ALS and frontotemporal dementia (FTD) and is found in ϳ7% of individuals with apparently sporadic disease. Several different diamino acid peptides can be generated from the HRE by noncanonical translation (repeat-associated non-ATG translation, or RAN translation), and some of these peptides can be toxic. Here, we studied the effects of two arginine containing RAN translation products [proline/arginine repeated 20 times (PR20) and glycine/arginine repeated 20 times (GR20)] in primary rat spinal cord neuron cultures grown on an astrocyte feeder layer. -
Machine Learning Models for Predicting Protein Condensate Formation from Sequence Determinants and Embeddings
bioRxiv preprint doi: https://doi.org/10.1101/2020.10.26.354753; this version posted October 26, 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-NC-ND 4.0 International license. Machine learning models for predicting protein condensate formation from sequence determinants and embeddings Kadi L. Saar,1;2;† Alexey S. Morgunov,1;3;† Runzhang Qi,1 William E. Arter,1 Georg Krainer,1 Alpha A. Lee2 & Tuomas P. J. Knowles1;2;∗ 1 Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK 2 Cavendish Laboratory, Department of Physics, University of Cambridge, J J Thomson Ave, Cambridge CB3 0HE, UK 3 Fluidic Analytics, Unit A, The Paddocks Business Centre, Cherry Hinton Rd, Cambridge CB1 8DH, UK † These authors contributed equally ∗ To whom correspondence should be addressed: [email protected] Abstract Intracellular phase separation of proteins into biomolecular condensates is increasingly recognised as an important phenomenon for cellular compartmentalisation and regulation of biological function. Different hypotheses about the parameters that determine the ten- dency of proteins to form condensates have been proposed with some of them probed ex- perimentally through the use of constructs generated by sequence alterations. To broaden the scope of these observations, here, we established an in silico strategy for understanding on a global level the associations between protein sequence and condensate formation, and used this information to construct machine learning classifiers for predicting liquid–liquid phase separation (LLPS) from protein sequence. -
C9orf72 Testing in a Diagnostic Laboratory Using the Asuragen Amplidex® PCR/CE C9orf72 Kit
C9orf72 testing in a diagnostic laboratory using the Asuragen AmplideX® PCR/CE C9orf72 kit Rick van Minkelen1, Patricia Reichgelt1, Saskia Theunisse2, Jody Salomon2, Kristen Culp3, Dept. Clinical Genetics Janne M. Papma4, Laura Donker Kaat4,5, John C. van Swieten4,6, Raoul van de Graaf1, Lies H. Hoefsloot1, Martina Wilke1 1 Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands 2 Sanbio B.V., Uden, the Netherlands 3 Asuragen, Inc., Austin, TX, USA 4 Department of Neurology, Erasmus MC, Rotterdam, the Netherlands 5 Department of Clinical Genetics, LUMC, Leiden, the Netherlands 6 Department of Clinical Genetics, VUMC, Amsterdam, the Netherlands [email protected] Introduction The pathogenic expanded hexanucleotide repeat element (G4C2) in intron 1 of the Chromosome 9 open reading frame 72 gene (C9orf72; Results NM_001256054.2) is the most prevalent genetic cause of the All samples previously scored as pathogenic using the home-made tests neurodegenerative disorders frontotemporal dementia (FTD) and also showed a pathogenic repeat expansion of at least 145 repeats using amyotrophic lateral sclerosis (ALS). Here we describe our experiences in the new Asuragen test (for examples see Figure 1). No repeats were sized using the newly introduced Asuragen AmplideX® PCR/CE C9orf72 assay in the range 60-145. Repeats in the normal range were sized exactly the compared to our home-made long range and repeat-primed PCR tests for same. DNA concentrations of 50ng/µl (our standard lab dilution) and the detection of C9orf72 repeats. Our home-made tests are limited to 25ng/µl showed similar results. A dilution (including a second 30s injection detection of up to ~60 C9orf72 repeats. -
Genetic Testing and Genetic Counseling for Amyotrophic Lateral Sclerosis: an Update for Clinicians
© American College of Medical Genetics and Genomics REVIEW Genetic testing and genetic counseling for amyotrophic lateral sclerosis: an update for clinicians Jennifer Roggenbuck, MS1, Adam Quick, MD1 and Stephen J. Kolb, MD, PhD1 Patients with amyotrophic lateral sclerosis (ALS) often have questions SOD1 antisense oligonucleotide trials. In the span of a few years, ALS about why they developed the disease and the likelihood that family genetic testing options have progressed from testing of a single gene members will also be affected. In recent years, providing answers to to multigene next-generation sequencing panels and whole-exome these questions has become more complex with the identification of sequencing. This article provides suggestions for genetic counseling multiple novel genes, the newly recognized etiologic link between ALS and genetic testing for ALS in this new environment. and frontotemporal dementia (FTD), and the increased availability of Genet Med advance online publication 18 August 2016 commercial genetic testing. A genetic diagnosis is particularly impor- tant to establish in the era of emerging gene-based therapies, such as Key Words: motor neuron disease; C9orf72 INTRODUCTION of novel genes, including C9orf72, the recognition of the link Amyotrophic lateral sclerosis (ALS) is an adult-onset neuro- between ALS and frontotemporal dementia (FTD), and the advent degenerative disorder characterized by loss of upper and lower of next-generation sequencing technology. The genetic basis of motor neurons, progressive paralysis, and death within an aver- two-thirds of fALS and 10% of sALS case has now been estab- age of 2–5 years after symptom onset. Diagnosis is based on lished. -
A Hexanucleotide Repeat Expansion in C9ORF72 Is the Cause of Chromosome 9P21-Linked ALS- FTD, Neuron (2011), Doi:10.1016/J.Neuron.2011.09.010 Neuron Article
Please cite this article in press as: Renton et al., A Hexanucleotide Repeat Expansion in C9ORF72 Is the Cause of Chromosome 9p21-Linked ALS- FTD, Neuron (2011), doi:10.1016/j.neuron.2011.09.010 Neuron Article AHexanucleotideRepeatExpansioninC9ORF72 Is the Cause of Chromosome 9p21-Linked ALS-FTD Alan E. Renton,1,38 Elisa Majounie,2,38 Adrian Waite,3,38 Javier Simo´ n-Sa´ nchez,4,5,38 Sara Rollinson,6,38 J. Raphael Gibbs,7,8,38 Jennifer C. Schymick,1,38 Hannu Laaksovirta,9,38 John C. van Swieten,4,5,38 Liisa Myllykangas,10 Hannu Kalimo,10 Anders Paetau,10 Yevgeniya Abramzon,1 Anne M. Remes,11 Alice Kaganovich,12 Sonja W. Scholz,2,13,14 Jamie Duckworth,7 Jinhui Ding,7 Daniel W. Harmer,15 Dena G. Hernandez,2,8 Janel O. Johnson,1,8 Kin Mok,8 Mina Ryten,8 Danyah Trabzuni,8 Rita J. Guerreiro,8 Richard W. Orrell,16 James Neal,17 Alex Murray,18 Justin Pearson,3 Iris E. Jansen,4 David Sondervan,4 Harro Seelaar,5 Derek Blake,3 Kate Young,6 Nicola Halliwell,6 Janis Bennion Callister,6 Greg Toulson,6 Anna Richardson,19 Alex Gerhard,19 Julie Snowden,19 David Mann,19 David Neary,19 Michael A. Nalls,2 Terhi Peuralinna,9 Lilja Jansson,9 Veli-Matti Isoviita,9 Anna-Lotta Kaivorinne,11 Maarit Ho¨ ltta¨ -Vuori,20 Elina Ikonen,20 Raimo Sulkava,21 Michael Benatar,22 Joanne Wuu,23 Adriano Chio` ,24 Gabriella Restagno,25 Giuseppe Borghero,26 Mario Sabatelli,27 The ITALSGEN Consortium,28 David Heckerman,29 Ekaterina Rogaeva,30 Lorne Zinman,31 Jeffrey D. -
The Ubiquitin Proteasome System in Neuromuscular Disorders: Moving Beyond Movement
International Journal of Molecular Sciences Review The Ubiquitin Proteasome System in Neuromuscular Disorders: Moving Beyond Movement 1, , 2, 3,4 Sara Bachiller * y , Isabel M. Alonso-Bellido y , Luis Miguel Real , Eva María Pérez-Villegas 5 , José Luis Venero 2 , Tomas Deierborg 1 , José Ángel Armengol 5 and Rocío Ruiz 2 1 Experimental Neuroinflammation Laboratory, Department of Experimental Medical Science, Lund University, Sölvegatan 19, 221 84 Lund, Sweden; [email protected] 2 Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla/Instituto de Biomedicina de Sevilla-Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, 41012 Sevilla, Spain; [email protected] (I.M.A.-B.); [email protected] (J.L.V.); [email protected] (R.R.) 3 Unidad Clínica de Enfermedades Infecciosas, Hospital Universitario de Valme, 41014 Sevilla, Spain; [email protected] 4 Departamento de Especialidades Quirúrgicas, Bioquímica e Inmunología, Facultad de Medicina, 29071 Universidad de Málaga, Spain 5 Departamento de Fisiología, Anatomía y Biología Celular, Universidad Pablo de Olavide, 41013 Sevilla, Spain; [email protected] (E.M.P.-V.); [email protected] (J.Á.A.) * Correspondence: [email protected] These authors contributed equally to the work. y Received: 14 July 2020; Accepted: 31 August 2020; Published: 3 September 2020 Abstract: Neuromuscular disorders (NMDs) affect 1 in 3000 people worldwide. There are more than 150 different types of NMDs, where the common feature is the loss of muscle strength. These disorders are classified according to their neuroanatomical location, as motor neuron diseases, peripheral nerve diseases, neuromuscular junction diseases, and muscle diseases. Over the years, numerous studies have pointed to protein homeostasis as a crucial factor in the development of these fatal diseases. -
Disrupted Neuronal Trafficking in Amyotrophic Lateral Sclerosis
Acta Neuropathologica (2019) 137:859–877 https://doi.org/10.1007/s00401-019-01964-7 REVIEW Disrupted neuronal trafcking in amyotrophic lateral sclerosis Katja Burk1,2 · R. Jeroen Pasterkamp3 Received: 12 October 2018 / Revised: 19 January 2019 / Accepted: 19 January 2019 / Published online: 5 February 2019 © The Author(s) 2019 Abstract Amyotrophic lateral sclerosis (ALS) is a progressive, adult-onset neurodegenerative disease caused by degeneration of motor neurons in the brain and spinal cord leading to muscle weakness. Median survival after symptom onset in patients is 3–5 years and no efective therapies are available to treat or cure ALS. Therefore, further insight is needed into the molecular and cellular mechanisms that cause motor neuron degeneration and ALS. Diferent ALS disease mechanisms have been identi- fed and recent evidence supports a prominent role for defects in intracellular transport. Several diferent ALS-causing gene mutations (e.g., in FUS, TDP-43, or C9ORF72) have been linked to defects in neuronal trafcking and a picture is emerging on how these defects may trigger disease. This review summarizes and discusses these recent fndings. An overview of how endosomal and receptor trafcking are afected in ALS is followed by a description on dysregulated autophagy and ER/ Golgi trafcking. Finally, changes in axonal transport and nucleocytoplasmic transport are discussed. Further insight into intracellular trafcking defects in ALS will deepen our understanding of ALS pathogenesis and will provide novel avenues for therapeutic intervention. Keywords Amyotrophic lateral sclerosis · Motor neuron · Trafcking · Cytoskeleton · Rab Introduction onset is about 10 years earlier [44]. As disease progresses, corticospinal motor neurons, projecting from the motor cor- Amyotrophic lateral sclerosis (ALS) is a fatal disease char- tex to the brainstem and spinal cord, and bulbar and spinal acterized by the degeneration of upper and lower motor motor neurons, projecting to skeletal muscles, degenerate. -
Structural Basis for VPS34 Kinase Activation by Rab1 and Rab5 on Membranes
ARTICLE https://doi.org/10.1038/s41467-021-21695-2 OPEN Structural basis for VPS34 kinase activation by Rab1 and Rab5 on membranes Shirley Tremel 1, Yohei Ohashi 1, Dustin R. Morado1,2, Jessie Bertram1, Olga Perisic 1, Laura T. L. Brandt 1, Marie-Kristin von Wrisberg 3, Zhuo A. Chen 4, Sarah L. Maslen 1, Oleksiy Kovtun 1, Mark Skehel 1, ✉ ✉ ✉ Juri Rappsilber4,5, Kathrin Lang 3, Sean Munro 1 , John A. G. Briggs 1 & Roger L. Williams 1 The lipid phosphatidylinositol-3-phosphate (PI3P) is a regulator of two fundamental but 1234567890():,; distinct cellular processes, endocytosis and autophagy, so its generation needs to be under precise temporal and spatial control. PI3P is generated by two complexes that both contain the lipid kinase VPS34: complex II on endosomes (VPS34/VPS15/Beclin 1/UVRAG), and complex I on autophagosomes (VPS34/VPS15/Beclin 1/ATG14L). The endosomal GTPase Rab5 binds complex II, but the mechanism of VPS34 activation by Rab5 has remained elusive, and no GTPase is known to bind complex I. Here we show that Rab5a–GTP recruits endocytic complex II to membranes and activates it by binding between the VPS34 C2 and VPS15 WD40 domains. Electron cryotomography of complex II on Rab5a-decorated vesicles shows that the VPS34 kinase domain is released from inhibition by VPS15 and hovers over the lipid bilayer, poised for catalysis. We also show that the GTPase Rab1a, which is known to be involved in autophagy, recruits and activates the autophagy-specific complex I, but not complex II. Both Rabs bind to the same VPS34 interface but in a manner unique for each. -
C9orf72 Frontotemporal Dementia and Amyotrophic Lateral Sclerosis: Investigating Repeat Pathology in Cell Culture Models and Human Post-Mortem Brain
C9orf72 frontotemporal dementia and amyotrophic lateral sclerosis: investigating repeat pathology in cell culture models and human post-mortem brain. Charlotte Elizabeth Ridler A thesis submitted in partial fulfilment of the requirements for the degree of Doctor of Philosophy from University College London Department of Neurodegenerative Disease Institute of Neurology University College London 2016 1 Declaration I, Charlotte Ridler, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. 2 Acknowledgements My deepest thanks go to everyone who has helped and supported me during this PhD project, without whom it would not have been possible. Thank you firstly to my supervisor Dr. Adrian Isaacs for all of his guidance, encouragement and enthusiastic discussions during this exciting and unpredictable project. Thank you also to Dr. Sarah Mizielinska, who has been an incredible mentor and role-model during this PhD; I have learnt a huge amount from her endless dedication and generosity. I would also like to thank my secondary supervisor Prof. Elizabeth Fisher for all her wise words of advice. Thank you to all members of the Isaacs and Fisher labs past and present. Special thanks to Frances Norona, Dr. Karen Cleverly, Julian Pietrzyk, Dr. Ione Woollacott and Dr. Anny Devoy who were all great help during the cloning phase of this project; to Dr. Rubika Balendra for all her help and discussions in the nucleoli work; and to Dr. Emma Clayton and Dr. Roberto Simone for their constant support. A number of other people have lent me their valuable expertise for this project, for which I am very grateful. -
Aggresomal Sequestration and STUB1-Mediated Ubiquitylation During Mammalian Proteaphagy of Inhibited Proteasomes
Aggresomal sequestration and STUB1-mediated ubiquitylation during mammalian proteaphagy of inhibited proteasomes Won Hoon Choia,b, Yejin Yuna,b, Seoyoung Parka,c, Jun Hyoung Jeona,b, Jeeyoung Leea,b, Jung Hoon Leea,c, Su-A Yangd, Nak-Kyoon Kime, Chan Hoon Jungb, Yong Tae Kwonb, Dohyun Hanf, Sang Min Lime, and Min Jae Leea,b,c,1 aDepartment of Biochemistry and Molecular Biology, Seoul National University College of Medicine, 03080 Seoul, Korea; bDepartment of Biomedical Sciences, Seoul National University Graduate School, 03080 Seoul, Korea; cNeuroscience Research Institute, Seoul National University College of Medicine, 03080 Seoul, Korea; dScience Division, Tomocube, 34109 Daejeon, Korea; eConvergence Research Center for Diagnosis, Korea Institute of Science and Technology, 02792 Seoul, Korea; and fProteomics Core Facility, Biomedical Research Institute, Seoul National University Hospital, 03080 Seoul, Korea Edited by Richard D. Vierstra, Washington University in St. Louis, St. Louis, MO, and approved July 1, 2020 (received for review November 18, 2019) The 26S proteasome, a self-compartmentalized protease complex, additional LC3-interacting region; the target cargoes can be plays a crucial role in protein quality control. Multiple levels of docked onto phosphatidylethanolamine-modified LC3 (LC3-II) regulatory systems modulate proteasomal activity for substrate on the expanding phagophore membrane, enveloped by an hydrolysis. However, the destruction mechanism of mammalian autophagosome, and eventually degraded in the autolysosomes. proteasomes is poorly understood. We found that inhibited pro- Notably, the enzymatic cascade attaching the lipid moiety at the teasomes are sequestered into the insoluble aggresome via C-terminal glycine of the cleaved LC3 protein in autophagy re- HDAC6- and dynein-mediated transport. -
RTL8 Promotes Nuclear Localization of UBQLN2 to Subnuclear Compartments Associated with Protein Quality Control
bioRxiv preprint doi: https://doi.org/10.1101/2021.04.21.440788; this version posted April 22, 2021. 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. Title: RTL8 promotes nuclear localization of UBQLN2 to subnuclear compartments associated with protein quality control Harihar Milaganur Mohan1,2, Amit Pithadia1, Hanna Trzeciakiewicz1, Emily V. Crowley1, Regina Pacitto1 Nathaniel Safren1,3, Chengxin Zhang4, Xiaogen Zhou4, Yang Zhang4, Venkatesha Basrur5, Henry L. Paulson1,*, Lisa M. Sharkey1,* 1. Department of Neurology, University of Michigan, Ann Arbor, MI 48109-2200 2. Graduate Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI 48109- 2200 3. Present address: Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611 4. Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109-2200 5. Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109. *Corresponding authors: Henry Paulson: Department of Neurology, University of Michigan, Ann Arbor, MI 48109-2200; [email protected]; Tel. (734) 615-5632; Fax. (734) 615-5655 Lisa M Sharkey: Department of Neurology, University of Michigan, Ann Arbor, MI 48109-2200; [email protected]; Tel. (734) 763-3496; Fax (734) 615-5655 Keywords: Ubiquilin, UBQLN2, RTL8, Nuclear Protein Quality Control, Ubiquitin Proteasome System Declarations Funding: This work was supported by NIH 9R01NS096785-06, 1P30AG053760-01, The Amyotrophic Lateral Sclerosis Foundation and the UM Protein Folding Disease Initiative. Conflicts of interest/Competing interests: None declared Availability of data and material: • The authors confirm that the data supporting the findings in this are available within the article, at repository links provided within the article, and within its supplementary files.