Login to MyKarger

New to MyKarger? Click here to sign up.



Login with Facebook

Forgot your password?

Authors, Editors, Reviewers

For Manuscript Submission, Check or Review Login please go to Submission Websites List.

Submission Websites List

Institutional Login
(Shibboleth or Open Athens)

For the academic login, please select your country in the dropdown list. You will be redirected to verify your credentials.

Original Paper

Inhibition of Pathogenic Mutant SOD1 Aggregation in Cultured Motor Neuronal Cells by Prevention of Its SUMOylation on Lysine 75

Dangoumau A.a · Marouillat S.a · Burlaud Gaillard J.b · Uzbekov R.b · Veyrat-Durebex C.a · Blasco H.a, d · Arnoult C.c · Corcia P.a, e · Andres C.R.a, d · Vourc'h P.a,b,d

Author affiliations

aUMR INSERM U930, bPST Analyse des Systèmes Biologiques and cCNRS UMR 7292, Université François-Rabelais, dCHRU de Tours, Laboratoire de Biochimie et de Biologie Moléculaire, and eCentre SLA, CHRU de Tours, Hôpital Bretonneau, Tours, France

Related Articles for ""

Neurodegener Dis 2016;16:161-171

Do you have an account?

Login Information





Contact Information










I have read the Karger Terms and Conditions and agree.



Login Information





Contact Information










I have read the Karger Terms and Conditions and agree.



To view the fulltext, please log in

To view the pdf, please log in

Buy

  • FullText & PDF
  • Unlimited re-access via MyKarger
  • Unrestricted printing, no saving restrictions for personal use
read more

CHF 38.00 *
EUR 35.00 *
USD 39.00 *

Select

KAB

Buy a Karger Article Bundle (KAB) and profit from a discount!

If you would like to redeem your KAB credit, please log in.


Save over 20% compared to the individual article price.
Learn more

Rent/Cloud

  • Rent for 48h to view
  • Buy Cloud Access for unlimited viewing via different devices
  • Synchronizing in the ReadCube Cloud
  • Printing and saving restrictions apply

Rental: USD 8.50
Cloud: USD 20.00


Select

Subscribe

  • Access to all articles of the subscribed year(s) guaranteed for 5 years
  • Unlimited re-access via Subscriber Login or MyKarger
  • Unrestricted printing, no saving restrictions for personal use
read more

Subcription rates


Select

* The final prices may differ from the prices shown due to specifics of VAT rules.

Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: April 10, 2015
Accepted: August 07, 2015
Published online: November 26, 2015
Issue release date: April 2016

Number of Print Pages: 11
Number of Figures: 5
Number of Tables: 0

ISSN: 1660-2854 (Print)
eISSN: 1660-2862 (Online)

For additional information: https://www.karger.com/NDD

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective death of motor neurons. Mutations in the SOD1 gene encoding the superoxide dismutase 1 are present in 15% of familial ALS cases and in 2% of sporadic cases. These mutations are associated with the formation of SOD1-positive aggregates. The mechanisms of aggregation remain unknown, but posttranslational modifications of SOD1 may be involved. Here, we report that NSC-34 motor neuronal cells expressing mutant SOD1 contained aggregates positive for small ubiquitin modifier-1 (SUMO-1), and in parallel a reduced level of free SUMO-1. CLEM (correlative light and electron microscopy) analysis showed nonorganized cytosolic aggregates for all mutations tested (SOD1A4V, SOD1V31A, and SOD1G93C). We next show that preventing the SUMOylation of mutant SOD1 by the substitution of lysine 75, the SUMOylation site of SOD1, significantly reduces the number of motor neuronal cells with aggregates. These results support the need for further research on the SUMOylation pathways, which may be a potential therapeutic target in ALS.

© 2015 S. Karger AG, Basel


References

  1. Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A, et al: Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 1993;362:59-62.
  2. Deng HX, Hentati A, Tainer JA, Iqbal Z, Cayabyab A, Hung WY, et al: Amyotrophic lateral sclerosis and structural defects in Cu,Zn superoxide dismutase. Science 1993;261:1047-1051.
  3. Andersen PM, Al-Chalabi A: Clinical genetics of amyotrophic lateral sclerosis: what do we really know? Nat Rev Neurol 2011;7:603-615.
  4. Gurney ME, Cutting FB, Zhai P, Andrus PK, Hall ED: Pathogenic mechanisms in familial amyotrophic lateral sclerosis due to mutation of Cu,Zn superoxide dismutase. Pathol Biol (Paris) 1996;44:51-56.
    External Resources
  5. Reaume AG, Elliott JL, Hoffman EK, Kowall NW, Ferrante RJ, Siwek DF, et al: Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop normally but exhibit enhanced cell death after axonal injury. Nat Genet 1996;13:43-47.
  6. Bruijn LI, Houseweart MK, Kato S, Anderson KL, Anderson SD, Ohama E, et al: Aggregation and motor neuron toxicity of an ALS-linked SOD1 mutant independent from wild-type SOD1. Science 1998;281:1851-1854.
  7. Son M, Cloyd CD, Rothstein JD, Rajendran B, Elliott JL: Aggregate formation in Cu,Zn superoxide dismutase-related proteins. J Biol Chem 2003;278:14331-14336.
  8. Watanabe M, Dykes-Hoberg M, Culotta VC, Price DL, Wong PC, Rothstein JD: Histological evidence of protein aggregation in mutant SOD1 transgenic mice and in amyotrophic lateral sclerosis neural tissues. Neurobiol Dis 2001;8:933-941.
  9. Zhang F, Zhu H: Intracellular conformational alterations of mutant SOD1 and the implications for fALS-associated SOD1 mutant induced motor neuron cell death. Biochim Biophys Acta 2006;1760:404-414.
  10. Taylor JP, Hardy J, Fischbeck KH: Toxic proteins in neurodegenerative disease. Science 2002;296:1991-1995.
  11. Gareau JR, Lima CD: The SUMO pathway: emerging mechanisms that shape specificity, conjugation and recognition. Nat Rev Mol Cell Biol 2010;11:861-871.
  12. Dangoumau A, Veyrat-Durebex C, Blasco H, Praline J, Corcia P, Andres CR, et al: Protein SUMOylation, an emerging pathway in amyotrophic lateral sclerosis. Int J Neurosci 2013;123:366-374.
  13. Fei E, Jia N, Yan M, Ying Z, Sun Q, Wang H, et al: SUMO-1 modification increases human SOD1 stability and aggregation. Biochem Biophys Res Commun 2006;347:406-412.
  14. Niikura T, Kita Y, Abe Y: SUMO3 modification accelerates the aggregation of ALS-linked SOD1 mutants. PLoS One 2014;9:e101080.
  15. Lamb AL1, Wernimont AK, Pufahl RA, Culotta VC, OʼHalloran TV, Rosenzweig AC: Crystal structure of the copper chaperone for superoxide dismutase. Nat Struct Biol 1999;6:724-729.
  16. Arnold K, Bordoli L, Kopp J, Schwede T: The SWISS-MODEL workspace: a web-based environment for protein structure homology modelling. Bioinformatics 2006;22:195-201.
  17. Dangoumau A, Verschueren A, Hammouche E, Papon M-A, Blasco H, Cherpi-Antar C, et al: Novel SOD1 mutation p.V31A identified with a slowly progressive form of amyotrophic lateral sclerosis. Neurobiol Aging 2014;35:266.e1-e4.
  18. Boutahar N, Wierinckx A, Camdessanche JP, Antoine J-C, Reynaud E, Lassabliere F, et al: Differential effect of oxidative or excitotoxic stress on the transcriptional profile of amyotrophic lateral sclerosis-linked mutant SOD1 cultured neurons. J Neurosci Res 2011;89:1439-1450.
  19. Kirby J, Halligan E, Baptista MJ, Allen S, Heath PR, Holden H, et al: Mutant SOD1 alters the motor neuronal transcriptome: implications for familial ALS. Brain J Neurol 2005;128:1686-1706.
  20. Sau D, De Biasi S, Vitellaro-Zuccarello L, Riso P, Guarnieri S, Porrini M, et al: Mutation of SOD1 in ALS: a gain of a loss of function. Hum Mol Genet 2007;16:1604-1618.
  21. Broom WJ, Russ C, Sapp PC, McKenna-Yasek D, Hosler BA, Andersen PM, et al: Variants in candidate ALS modifier genes linked to Cu/Zn superoxide dismutase do not explain divergent survival phenotypes. Neurosci Lett 2006;392:52-57.
  22. Kim YM, Jang WH, Quezado MM, Oh Y, Chung KC, Junn E, et al: Proteasome inhibition induces α-synuclein SUMOylation and aggregate formation. J Neurol Sci 2011;307:157-161.
  23. Dorval V, Fraser PE: SUMO on the road to neurodegeneration. Biochim Biophys Acta 2007;1773:694-706.
  24. Krumova P, Weishaupt JH: SUMOylation in neurodegenerative diseases. Cell Mol Life Sci 2013;70:2123-2138.
  25. Seyfried NT, Gozal YM, Dammer EB, Xia Q, Duong DM, Cheng D, et al: Multiplex SILAC analysis of a cellular TDP-43 proteinopathy model reveals protein inclusions associated with SUMOylation and diverse polyubiquitin chains. Mol Cell Proteomics 2010;9:705-718.
  26. Bergink S, Jentsch S: Principles of ubiquitin and SUMO modifications in DNA repair. Nature 2009;458:461-467.
  27. Jaafari N, Konopacki FA, Owen TF, Kantamneni S, Rubin P, Craig TJ, et al: SUMOylation is required for glycine-induced increases in AMPA receptor surface expression (ChemlTP) in hippocampal neurons. PLoS One 2013;8:e52345.
  28. Kirkin V, Dikic I: Role of ubiquitin- and Ubl-binding proteins in cell signaling. Curr Opin Cell Biol 2007;19:199-205.
  29. Rodriguez JA, Valentine JS, Eggers DK, Roe JA, Tiwari A, Brown RH, et al: Familial amyotrophic lateral sclerosis-associated mutations decrease the thermal stability of distinctly metallated species of human copper/zinc superoxide dismutase. J Biol Chem 2002;277:15932-15937.
  30. Williamson TL, Corson LB, Huang L, Burlingame A, Liu J, Bruijn LI, et al: Toxicity of ALS-linked SOD1 mutants. Science 2000;288:399.
  31. Novoselov SS, Mustill WJ, Gray AL, Dick JR, Kanuga N, Kalmar B, et al: Molecular chaperone mediated late-stage neuroprotection in the SOD1G93A mouse model of amyotrophic lateral sclerosis. PLoS One 2013;8:e73944.
  32. Mukherjee S, Thomas M, Dadgar N, Lieberman AP, Iñiguez-Lluhí JA: Small ubiquitin-like modifier (SUMO) modification of the androgen receptor attenuates polyglutamine-mediated aggregation. J Biol Chem 2009;284:21296-21306.
  33. O'Rourke JG, Gareau JR, Ochaba J, Song W, Raskó T, Reverter D, et al: SUMO-2 and PIAS1 modulate insoluble mutant huntingtin protein accumulation. Cell Rep 2013;4:362-375.

Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: April 10, 2015
Accepted: August 07, 2015
Published online: November 26, 2015
Issue release date: April 2016

Number of Print Pages: 11
Number of Figures: 5
Number of Tables: 0

ISSN: 1660-2854 (Print)
eISSN: 1660-2862 (Online)

For additional information: https://www.karger.com/NDD


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.