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Table of Contents
Vol. 16, No. 1, 2008
Issue release date: December 2007
Section title: Paper
Neurosignals 2008;16:41–51
(DOI:10.1159/000109758)

TDP-43 Proteinopathies: Neurodegenerative Protein Misfolding Diseases without Amyloidosis

Kwong L.K.a · Uryu K.a · Trojanowski J.Q.a, b · Lee V.M.-Y.a, b
aCenter for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, and bInstitute on Aging, University of Pennsylvania School of Medicine, Philadelphia, Pa., USA
email Corresponding Author

Abstract

In this review, we summarize recent advances in understanding frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS) and related neurodegenerative disorders that are collectively known as TDP-43 proteinopathies, since transactive response DNA-binding protein 43 (TDP-43) was recently shown to be the major component of the ubiquitinated inclusions that are their pathological hallmarks. TDP-43 proteinopathies are distinct from most other neurodegenerative disorders because TDP-43 inclusions are not amyloid deposits. Besides TDP-43-positive inclusions, both sporadic and familial forms of FTLD and ALS have the pathologic TDP-43 signature of abnormal hyperphosphorylation, ubiquitination and C-terminal fragments in affected brain and spinal cord, suggesting that they share a common mechanism of pathogenesis. Thus, these findings support the concept that FTLD and ALS represent a clinicopathologic spectrum of one disease, that is, TDP-43 proteinopathy.

© 2008 S. Karger AG, Basel


  

Key Words

  • TDP-43
  • Frontotemporal lobar degeneration
  • Amyotrophic lateral sclerosis
  • Neurodegenerative disease
  • Frontotemporal dementia

References

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  2. Ratnavalli E, Brayne C, Dawson K, Hodges JR: The prevalence of frontotemporal dementia. Neurology 2002;58:1615–1621.
  3. Neary D, Snowden JS, Gustafson L, Passant U, Stuss D, Black S, Freedman M, Kertesz A, Robert PH, Albert M, Boone K, Miller BL, Cummings J, Benson DF: Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 1998;51:1546–1554.
  4. Forman MS, Farmer J, Johnson JK, Clark CM, Arnold SE, Coslett HB, Chatterjee A, Hurtig HI, Karlawish JH, Rosen HJ, Van D, V, Lee VM, Miller BL, Trojanowski JQ, Grossman M: Frontotemporal dementia: clinicopathological correlations. Ann Neurol 2006;59:952–962.
  5. Kertesz A, Munoz DG: Frontotemporal dementia. Med Clin North Am 2002;86:501–518.
  6. Lomen-Hoerth C, Anderson T, Miller B: The overlap of amyotrophic lateral sclerosis and frontotemporal dementia. Neurology 2002;59:1077–1079.
  7. Hodges JR, Davies RR, Xuereb JH, Casey B, Broe M, Bak TH, Kril JJ, Halliday GM: Clinicopathological correlates in frontotemporal dementia. Ann Neurol 2004;56:399–406.
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  9. Lipton AM, White CL III, Bigio EH: Frontotemporal lobar degeneration with motor neuron disease-type inclusions predominates in 76 cases of frontotemporal degeneration. Acta Neuropathol (Berl) 2004;108:379–385.
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    External Resources

  11. Baker M, Mackenzie IR, Pickering-Brown SM, Gass J, Rademakers R, Lindholm C, Snowden J, Adamson J, Sadovnick AD, Rollinson S, Cannon A, Dwosh E, Neary D, Melquist S, Richardson A, Dickson D, Berger Z, Eriksen J, Robinson T, Zehr C, Dickey CA, Crook R, McGowan E, Mann D, Boeve B, Feldman H, Hutton M: Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 2006;442:916–919.
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    External Resources

  18. Ou SH, Wu F, Harrich D, Garcia-Martinez LF, Gaynor RB: Cloning and characterization of a novel cellular protein, TDP-43, that binds to human immunodeficiency virus type 1 TAR DNA sequence motifs. J Virol 1995;69:3584–3596.
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    External Resources

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    External Resources

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Author Contacts

Virginia M.-Y. Lee, PhD, Center for Neurodegenerative Disease Research
Department of Pathology and Laboratory Medicine
University of Pennsylvania School of Medicine, HUP, Maloney 3rd Floor
36th and Spruce Streets, Philadelphia, PA 19104-4283 (USA)
Tel. +1 215 662 6399, Fax +1 215 349 5909, E-Mail vmylee@mail.med.upenn.edu

  

Article Information

Published online: December 5, 2007
Number of Print Pages : 11
Number of Figures : 2, Number of Tables : 0, Number of References : 59

  

Publication Details

Neurosignals

Vol. 16, No. 1, Year 2008 (Cover Date: December 2007)

Journal Editor: Ip, N.Y. (Hong Kong)
ISSN: 1424–862X (print), 1424–8638 (Online)

For additional information: http://www.karger.com/NSG


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 or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
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 goverment 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.

Abstract

In this review, we summarize recent advances in understanding frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS) and related neurodegenerative disorders that are collectively known as TDP-43 proteinopathies, since transactive response DNA-binding protein 43 (TDP-43) was recently shown to be the major component of the ubiquitinated inclusions that are their pathological hallmarks. TDP-43 proteinopathies are distinct from most other neurodegenerative disorders because TDP-43 inclusions are not amyloid deposits. Besides TDP-43-positive inclusions, both sporadic and familial forms of FTLD and ALS have the pathologic TDP-43 signature of abnormal hyperphosphorylation, ubiquitination and C-terminal fragments in affected brain and spinal cord, suggesting that they share a common mechanism of pathogenesis. Thus, these findings support the concept that FTLD and ALS represent a clinicopathologic spectrum of one disease, that is, TDP-43 proteinopathy.

© 2008 S. Karger AG, Basel


  

Author Contacts

Virginia M.-Y. Lee, PhD, Center for Neurodegenerative Disease Research
Department of Pathology and Laboratory Medicine
University of Pennsylvania School of Medicine, HUP, Maloney 3rd Floor
36th and Spruce Streets, Philadelphia, PA 19104-4283 (USA)
Tel. +1 215 662 6399, Fax +1 215 349 5909, E-Mail vmylee@mail.med.upenn.edu

  

Article Information

Published online: December 5, 2007
Number of Print Pages : 11
Number of Figures : 2, Number of Tables : 0, Number of References : 59

  

Publication Details

Neurosignals

Vol. 16, No. 1, Year 2008 (Cover Date: December 2007)

Journal Editor: Ip, N.Y. (Hong Kong)
ISSN: 1424–862X (print), 1424–8638 (Online)

For additional information: http://www.karger.com/NSG


Article / Publication Details

First-Page Preview
Abstract of Paper

Published online: 12/5/2007
Issue release date: December 2007

Number of Print Pages: 11
Number of Figures: 2
Number of Tables: 0

ISSN: 1424-862X (Print)
eISSN: 1424-8638 (Online)

For additional information: http://www.karger.com/NSG


Copyright / Drug Dosage

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 or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
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 goverment 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.

References

  1. Harvey RJ, Skelton-Robinson M, Rossor MN: The prevalence and causes of dementia in people under the age of 65 years. J Neurol Neurosurg Psychiatry 2003;74:1206–1209.
  2. Ratnavalli E, Brayne C, Dawson K, Hodges JR: The prevalence of frontotemporal dementia. Neurology 2002;58:1615–1621.
  3. Neary D, Snowden JS, Gustafson L, Passant U, Stuss D, Black S, Freedman M, Kertesz A, Robert PH, Albert M, Boone K, Miller BL, Cummings J, Benson DF: Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 1998;51:1546–1554.
  4. Forman MS, Farmer J, Johnson JK, Clark CM, Arnold SE, Coslett HB, Chatterjee A, Hurtig HI, Karlawish JH, Rosen HJ, Van D, V, Lee VM, Miller BL, Trojanowski JQ, Grossman M: Frontotemporal dementia: clinicopathological correlations. Ann Neurol 2006;59:952–962.
  5. Kertesz A, Munoz DG: Frontotemporal dementia. Med Clin North Am 2002;86:501–518.
  6. Lomen-Hoerth C, Anderson T, Miller B: The overlap of amyotrophic lateral sclerosis and frontotemporal dementia. Neurology 2002;59:1077–1079.
  7. Hodges JR, Davies RR, Xuereb JH, Casey B, Broe M, Bak TH, Kril JJ, Halliday GM: Clinicopathological correlates in frontotemporal dementia. Ann Neurol 2004;56:399–406.
  8. Johnson JK, Diehl J, Mendez MF, Neuhaus J, Shapira JS, Forman M, Chute DJ, Roberson ED, Pace-Savitsky C, Neumann M, Chow TW, Rosen HJ, Forstl H, Kurz A, Miller BL: Frontotemporal lobar degeneration: demographic characteristics of 353 patients. Arch Neurol 2005;62:925–930.
  9. Lipton AM, White CL III, Bigio EH: Frontotemporal lobar degeneration with motor neuron disease-type inclusions predominates in 76 cases of frontotemporal degeneration. Acta Neuropathol (Berl) 2004;108:379–385.
  10. Shi J, Shaw CL, Du PD, Richardson AM, Bailey KL, Julien C, Stopford C, Thompson J, Varma A, Craufurd D, Tian J, Pickering-Brown S, Neary D, Snowden JS, Mann DM: Histopathological changes underlying frontotemporal lobar degeneration with clinicopathological correlation. Acta Neuropathol (Berl) 2005;110:501–512.

    External Resources

  11. Baker M, Mackenzie IR, Pickering-Brown SM, Gass J, Rademakers R, Lindholm C, Snowden J, Adamson J, Sadovnick AD, Rollinson S, Cannon A, Dwosh E, Neary D, Melquist S, Richardson A, Dickson D, Berger Z, Eriksen J, Robinson T, Zehr C, Dickey CA, Crook R, McGowan E, Mann D, Boeve B, Feldman H, Hutton M: Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 2006;442:916–919.
  12. Cruts M, Gijselinck I, van der ZJ, Engelborghs S, Wils H, Pirici D, Rademakers R, Vandenberghe R, Dermaut B, Martin JJ, van Duijn C, Peeters K, Sciot R, Santens P, De Pooter T, Mattheijssens M, Van den BM, Cuijt I, Vennekens K, De Deyn PP, Kumar-Singh S, Van Broeckhoven C: Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature 2006;442:920–924.
  13. Forman MS, Mackenzie IR, Cairns NJ, Swanson E, Boyer PJ, Drachman DA, Jhaveri BS, Karlawish JH, Pestronk A, Smith TW, Tu PH, Watts GD, Markesbery WR, Smith CD, Kimonis VE: Novel ubiquitin neuropathology in frontotemporal dementia with valosin-containing protein gene mutations. J Neuropathol Exp Neurol 2006;65:571–581.
  14. Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, Bruce J, Schuck T, Grossman M, Clark CM, McCluskey LF, Miller BL, Masliah E, Mackenzie IR, Feldman H, Feiden W, Kretzschmar HA, Trojanowski JQ, Lee VM: Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 2006;314:130–133.
  15. Skovronsky DM, Lee VM, Trojanowski JQ: Neurodegenerative diseases: new concepts of pathogenesis and their therapeutic implications. Annu Rev Pathol Mech Dis 2006;1:151–170.
  16. Sampathu DM, Neumann M, Kwong LK, Chou TT, Micsenyi M, Truax A, Bruce J, Grossman M, Trojanowski JQ, Lee VM: Pathological heterogeneity of frontotemporal lobar degeneration with ubiquitin-positive inclusions delineated by ubiquitin immunohistochemistry and novel monoclonal antibodies. Am J Pathol 2006;169:1343–1352.
  17. Mackenzie IR, Baborie A, Pickering-Brown S, Du PD, Jaros E, Perry RH, Neary D, Snowden JS, Mann DM: Heterogeneity of ubiquitin pathology in frontotemporal lobar degeneration: classification and relation to clinical phenotype. Acta Neuropathol (Berl) 2006;112:539–549.

    External Resources

  18. Ou SH, Wu F, Harrich D, Garcia-Martinez LF, Gaynor RB: Cloning and characterization of a novel cellular protein, TDP-43, that binds to human immunodeficiency virus type 1 TAR DNA sequence motifs. J Virol 1995;69:3584–3596.
  19. Buratti E, Dork T, Zuccato E, Pagani F, Romano M, Baralle FE: Nuclear factor TDP-43 and SR proteins promote in vitro and in vivo CFTR exon 9 skipping. EMBO J 2001;20:1774–1784.
  20. Buratti E, Brindisi A, Pagani F, Baralle FE: Nuclear factor TDP-43 binds to the polymorphic TG repeats in CFTR intron 8 and causes skipping of exon 9: a functional link with disease penetrance. Am J Hum Genet 2004;74:1322–1325.
  21. Acharya KK, Govind CK, Shore AN, Stoler MH, Reddi PP: cis-Requirement for the maintenance of round spermatid-specific transcription. Dev Biol 2006;295:781–790.
  22. Mercado PA, Ayala YM, Romano M, Buratti E, Baralle FE: Depletion of TDP 43 overrides the need for exonic and intronic splicing enhancers in the human apoA-II gene. Nucleic Acids Res 2005;33:6000–6010.
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