Journal Mobile Options
Table of Contents
Vol. 4, No. 2-3, 2007
Issue release date: June 2007
Section title: Paper
Neurodegenerative Dis 2007;4:227–235
(DOI:10.1159/000101847)

Frontotemporal Lobar Degeneration with Ubiquitin-Positive Inclusions: A Molecular Genetic Update

van der Zee J. · Gijselinck I. · Pirici D. · Kumar-Singh S. · Cruts M. · Van Broeckhoven C.
Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Laboratory of Neurogenetics, Institute Born-Bunge, and University of Antwerp, Antwerp, Belgium

Do you have an account?

Register and profit from personalized services (MyKarger) Login Information

Please create your User ID & Password





Contact Information









I have read the Karger Terms and Conditions and agree.

Register and profit from personalized services (MyKarger) Login Information

Please create your User ID & Password





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 (new!)
  • Unrestricted printing, no saving restrictions for personal use
  • Reduced rates with a PPV account
read more

Direct: USD 38.00
Account: USD 26.50

Select

Rent/Cloud

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

Rental: USD 8.50
Cloud: USD 20.00

Select

Subscribe

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

Subcription rates


Select


Article / Publication Details

First-Page Preview
Abstract of Paper

Received: 10/9/2006
Accepted: 5/12/2006
Published online: 6/29/2007

Number of Print Pages: 9
Number of Figures: 3
Number of Tables: 2

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

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

Abstract

Frontotemporal lobar degeneration (FTLD) is a clinically, pathologically and genetically highly complex disorder. In the last few years enormous progress has been made in dissecting the genetic etiology of FTLD. Mutations have been identified in the progranulin gene (PGRN), the charged multivesicular body protein 2B gene (CHMP2B) and the valosin-containing protein gene (VCP). Mutations in these genes all lead to FTLD pathology characterized by ubiquitin-immunoreactive neuronal cytoplasmic and intranuclear lentiform inclusions (FTLD-U). The similar pathology suggests that these genes may be connected trough a common disease pathway leading to neurodegeneration and the formation of these pathognomic inclusions. This review focuses on the molecular genetic processes underlying FTLD-U pathology.


Article / Publication Details

First-Page Preview
Abstract of Paper

Received: 10/9/2006
Accepted: 5/12/2006
Published online: 6/29/2007

Number of Print Pages: 9
Number of Figures: 3
Number of Tables: 2

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

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


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. 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.
  2. Ratnavalli E, Brayne C, Dawson K, Hodges JR: The prevalence of frontotemporal dementia. Neurology 2002;58:1615–1621.
  3. 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.
  4. 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.
  5. Josephs KA, Holton JL, Rossor MN, Godbolt AK, Ozawa T, Strand K, Khan N, Al Sarraj S, Revesz T: Frontotemporal lobar degeneration and ubiquitin immunohistochemistry. Neuropathol Appl Neurobiol 2004;30:369–373.
  6. 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.
  7. Mackenzie IRA, Feldman HH: Ubiquitin immunohistochemistry suggests classic motor neuron disease, motor neuron disease with dementia, and frontotemporal dementia of the motor neuron disease type represent a clinicopathologic spectrum. J Neuropathol Exp Neurol 2005;64:730–739.
  8. Taniguchi S, McDonagh AM, Pickering-Brown SM, Umeda Y, Iwatsubo T, Hasegawa M, Mann DM: The neuropathology of frontotemporal lobar degeneration with respect to the cytological and biochemical characteristics of tau protein. Neuropathol Appl Neurobiol 2004;30:1–18.
  9. Mann DM, McDonagh AM, Snowden J, Neary D, Pickering-Brown SM: Molecular classification of the dementias. Lancet 2000;355:626.
  10. 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.
  11. Chow TW, Miller BL, Hayashi VN, Geschwind DH: Inheritance of frontotemporal dementia. Arch Neurol 1999;56:817–822.
  12. Poorkaj P, Grossman M, Steinbart E, Payami H, Sadovnick A, Nochlin D, Tabira T, Trojanowski JQ, Borson S, Galasko D, Reich S, Quinn B, Schellenberg G, Bird TD: Frequency of tau gene mutations in familial and sporadic cases of non-Alzheimer dementia. Arch Neurol 2001;58:383–387.
  13. Rosso SM, Donker KL, Baks T, Joosse M, De Koning I, Pijnenburg Y, de Jong D, Dooijes D, Kamphorst W, Ravid R, Niermeijer MF, Verheij F, Kremer HP, Scheltens P, van Duijn CM, Heutink P, Van Swieten JC: Frontotemporal dementia in The Netherlands: patient characteristics and prevalence estimates from a population-based study. Brain 2003;126:2016–2022.
  14. Stevens M, van Duijn CM, Kamphorst W, de Knijff P, Heutink P, van Gool WA, Scheltens P, Ravid R, Oostra BA, Niermeijer MF, Van Swieten JC: Familial aggregation in frontotemporal dementia. Neurology 1998;50:1541–1545.
  15. Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S, Houlden H, Pickering-Brown S, Chakraverty S, Isaacs A, Grover A, Hackett J, Adamson J, Lincoln S, Dickson D, Davies P, Petersen RC, Stevens M, de Graaff E, Wauters E, van Baren J, Hillebrand M, Joosse M, Kwon JM, Nowotny P, Che LK, Norton J, Morris JC, Reed LA, Trojanowski J, Basun H, Lannfelt L, Neystat M, Fahn S, Dark F, Tannenberg T, Dodd PR, Hayward N, Kwok JB, Schofield PR, Andreadis A, Snowden J, Craufurd D, Neary D, Owen F, Oostra BA, Hardy J, Goate A, van Swieten J, Mann D, Lynch T, Heutink P: Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 1998;393:702–705.
  16. 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, Eriksen J, Robinson T, Zehr C, Dickey CA, 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.
  17. Cruts M, Gijselinck I, van der Zee J, 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 Broeck M, Cuyt 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.
  18. Skibinski G, Parkinson NJ, Brown JM, Chakrabarti L, Lloyd SL, Hummerich H, Nielsen JE, Hodges JR, Spillantini MG, Thusgaard T, Brandner S, Brun A, Rossor MN, Gade A, Johannsen P, Sorensen SA, Gydesen S, Fisher EM, Collinge J: Mutations in the endosomal ESCRTIII-complex subunit CHMP2B in frontotemporal dementia. Nat Genet 2005;37:806–808.
  19. Watts GD, Wymer J, Kovach MJ, Mehta SG, Mumm S, Darvish D, Pestronk A, Whyte MP, Kimonis VE: Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. Nat Genet 2004;36:377–381.
  20. Lendon CL, Lynch T, Norton J, McKeel DW, Jr., Busfield F, Craddock N, Chakraverty S, Gopalakrishnan G, Shears SD, Grimmett W, Wilhelmsen KC, Hansen L, Morris JC, Goate AM: Hereditary dysphasic disinhibition dementia: a frontotemporal dementia linked to 17q21–22. Neurology 1998;50:1546–1555.
  21. Rosso SM, Kamphorst W, de Graaf B, Willemsen R, Ravid R, Niermeijer MF, Spillantini MG, Heutink P, Van Swieten JC: Familial frontotemporal dementia with ubiquitin-positive inclusions is linked to chromosome 17q21–22. Brain 2001;124:1948–1957.
  22. Rademakers R, Cruts M, Dermaut B, Sleegers K, Rosso SM, Van den Broeck M, Backhovens H, van Swieten J, van Duijn CM, Van Broeckhoven C: Tau negative frontal lobe dementia at 17q21: significant fine mapping of the candidate region to a 4.8 cM interval. Mol Psychiatry 2002;7:1064–1074.
  23. van der Zee J, Rademakers R, Engelborghs S, Gijselinck I, Bogaerts V, Vandenberghe R, Santens P, Caekebeke J, De Pooter T, Peeters K, Lubke U, Van den Broeck M, Martin JJ, Cruts M, De Deyn PP, Van Broeckhoven C, Dermaut B: A Belgian ancestral haplotype harbours a highly prevalent mutation for 17q21-linked tau-negative FTLD. Brain 2006;129:841–852.
  24. Mackenzie IR, Baker M, West G, Woulfe J, Qadi N, Gass J, Cannon A, Adamson J, Feldman H, Lindholm C, Melquist S, Pettman R, Sadovnick AD, Dwosh E, Whiteheart SW, Hutton M, Pickering-Brown SM: A family with tau-negative frontotemporal dementia and neuronal intranuclear inclusions linked to chromosome 17. Brain 2006;129:853–867.
  25. Cruts M, Rademakers R, Gijselinck I, van der Zee J, Dermaut B, De Pooter T, De Rijk P, Del Favero J, Van Broeckhoven C: Genomic architecture of human 17q21 linked to frontotemporal dementia uncovers a highly homologous family of low copy repeats in the tau region. Hum Mol Genet 2005;14:1753–1762.
  26. Baker M, Litvan I, Houlden H, Adamson J, Dickson D, Perez-Tur J, Hardy J, Lynch T, Bigio E, Hutton M: Association of an extended haplotype in the tau gene with progressive supranuclear palsy. Hum Mol Genet 1999;8:711–715.
  27. Stefansson H, Helgason A, Thorleifsson G, Steinthorsdottir V, Masson G, Barnard J, Baker A, Jonasdottir A, Ingason A, Gudnadottir VG, Desnica N, Hicks A, Gylfason A, Gudbjartsson DF, Jonsdottir GM, Sainz J, Agnarsson K, Birgisdottir B, Ghosh S, Olafsdottir A, Cazier JB, Kristjansson K, Frigge ML, Thorgeirsson TE, Gulcher JR, Kong A, Stefansson K: A common inversion under selection in Europeans. Nat Genet 2005;37:129–137.
  28. Gijselinck I, Bogaerts V, Rademakers R, van der Zee J, Van Broeckhoven C, Cruts M: Visualization of MAPT inversion on stretched chromosomes of tau-negative frontotemporal dementia patients. Hum Mutat 2006;27:1057–1059.
  29. He Z, Bateman A: Progranulin (granulin-epithelin precursor, PC-cell-derived growth factor, acrogranin) mediates tissue repair and tumorigenesis. J Mol Med 2003;81:600–612.
  30. Daniel R, He Z, Carmichael KP, Halper J, Bateman A: Cellular localization of gene expression for progranulin. J Histochem Cytochem 2000;48:999–1009.
  31. He ZH, Ong CHP, Halper J, Bateman A: Progranulin is a mediator of the wound response. Nature Medicine 2003;9:225–229.
  32. Malaspina A, Kaushik N, de Belleroche J: Differential expression of 14 genes in amyotrophic lateral sclerosis spinal cord detected using gridded cDNA arrays. J Neurochem 2001;77:132–145.
  33. Mukherjee O, Pastor P, Cairns NJ, Chakraverty S, Kauwe JS, Shears S, Behrens MI, Budde J, Hinrichs AL, Norton J, Levitch D, Taylor-Reinwald L, Gitcho M, Tu PH, Tenenholz GL, Liscic RM, Armendariz J, Morris JC, Goate AM: HDDD2 is a familial frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions caused by a missense mutation in the signal peptide of progranulin. Ann Neurol 2006;60:314–322.
  34. Huey ED, Grafman J, Wassermann EM, Pietrini P, Tierney MC, Ghetti B, Spina S, Baker M, Hutton M, Elder JW, Berger SL, Heflin KA, Hardy J, Momeni P: Characteristics of frontotemporal dementia patients with a progranulin mutation. Ann Neurol 2006;60:374–380.
  35. Gass J, Cannon A, Mackenzie IR, Boeve B, Baker M, Adamson J, Crook R, Melquist S, Kuntz K, Petersen R, Josephs K, Brown SP, Graff-Radford N, Uitti R, Dickson D, Wzsolek Z, Gonzalez J, Beach TG, Bigio E, Johnson N, Weintraub S, Mesulam M, White CL III, Woodruff B, Caselli R, Hsiung GY, Feldman H, Knopman D, Hutton M, Rademakers R: Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration. Hum Mol Genet 2006;15:2988–3001.
  36. Bronner IF, Rizzu P, Seelaar H, van Mil SE, Anar B, Azmani A, Donker Kaat L, Rosso S, Heutink P, Van Swieten JC: Progranulin mutations in Dutch familial frontotemporal lobar degeneration. Eur J Hum Genet 2007; Epub.
  37. Le Ber I, van der Zee J, Hannequin D, Gijselinck I, Campion D, Puel M, Laquerriere A, De Pooter T, Camuzat A, Van den Broeck M, Dubois B, Sellal F, Lacomblez L, Vercelletto M, Duyckaerts C, Cruts M, Verpillat P, Van Broeckhoven C, Brice A, French Research Network on FTD/FTD-MND: PGRN gene mutations in both sporadic and familial frontotemporal dementia. Hum Mutat 2007; in press.
  38. Brown J, Ashworth A, Gydesen S, Sorensen A, Rossor M, Hardy J, Collinge J: Familial non-specific dementia maps to chromosome 3. Hum Mol Genet 1995;4:1625–1628.
  39. Holm I, Englund E, and the FReJA consortium. Ubiquitin positive inclusions in frontotemporal dementia linked to chromosome 3 (FTD-3). Abstract Book 16th Int Congrf Neuropathology, San Francisco, 2006.
  40. Babst M, Katzmann DJ, Estepa-Sabal EJ, Meerloo T, Emr SD: ESCRT-III: An endosome-associated heterooligomeric protein complex required for MVB sorting. Developmental Cell 2002;3:271–282.
  41. Parkinson N, Ince PG, Smith MO, Highley R, Skibinski G, Andersen PM, Morrison KE, Pall HS, Hardiman O, Collinge J, Shaw PJ, Fisher EM: ALS phenotypes with mutations in CHMP2B (charged multivesicular body protein 2B). Neurology 2006;67:1074–1077.
  42. Cannon A, Baker M, Boeve B, Josephs K, Knopman D, Petersen R, Parisi J, Dickison D, Adamson J, Snowden J, Neary D, Mann D, Hutton M, Pickering-Brown SM: CHMP2B mutations are not a common cause of frontotemporal lobar degeneration. Neurosci Lett 2006;398:83–84.
  43. Rizzu P, van Mil SE, Anar B, Rosso SM, Kaat LD, Heutink P, Van Swieten JC: CHMP2B mutations are not a cause of dementia in Dutch patients with familial and sporadic frontotemporal dementia. Am J Med Genet B Neuropsychiatr Genet 2006;141:944–946.
  44. Kovach MJ, Waggoner B, Leal SM, Gelber D, Khardori R, Levenstien MA, Shanks CA, Gregg G, Al Lozi MT, Miller T, Rakowicz W, Lopate G, Florence J, Glosser G, Simmons Z, Morris JC, Whyte MP, Pestronk A, Kimonis VE: Clinical delineation and localization to chromosome 9p13.3-p12 of a unique dominant disorder in four families: hereditary inclusion body myopathy, Paget disease of bone, and frontotemporal dementia. Mol Genet Metab 2001;74:458–475.
  45. 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.
  46. Rabinovich E, Kerem A, Frohlich KU, Diamant N, Bar-Nun S: AAA-ATPase p97/Cdc48p, a cytosolic chaperone required for endoplasmic reticulum-associated protein degradation. Mol Cell Biol 2002;22:626–634.
  47. Ye Y, Meyer HH, Rapoport TA: The AAA ATPase Cdc48/p97 and its partners transport proteins from the ER into the cytosol. Nature 2001;414:652–656.
  48. DeLaBarre B, Brunger AT: Complete structure of p97/valosin-containing protein reveals communication between nucleotide domains. Nat Struct Biol 2003;10:856–863.
  49. Guyant-Marechal L, Laquerriere A, Duyckaerts C, Dumanchin C, Bou J, Dugny F, Le B, I, Frebourg T, Hannequin D, Campion D: Valosin-containing protein gene mutations: clinical and neuropathologic features. Neurology 2006;67:644–651.
  50. Schroder R, Watts GD, Mehta SG, Evert BO, Broich P, Fliessbach K, Pauls K, Hans VH, Kimonis V, Thal DR: Mutant valosin-containing protein causes a novel type of frontotemporal dementia. Ann Neurol 2005;57:457–461.
  51. Pirici D, Vandenberghe R, Rademakers R, Dermaut B, Cruts M, Vennekens K, Cuijt I, Lubke U, Ceuterick C, Martin JJ, Van Broeckhoven C, Kumar-Singh S: Characterization of ubiquitinated intraneuronal inclusions in a novel Belgian frontotemporal lobar degeneration family. J Neuropathol Exp Neurol 2006;65:289–301.
  52. Weihl CC, Dalal S, Pestronk A, Hanson PI: Inclusion body myopathy associated mutations in p97/VCP impair endoplasmic reticulum associated degradation. Hum Mol Genet 2006;15:189–199.