Skip to main content

Advertisement

SpringerLink
Log in

Valosin-containing protein and the pathogenesis of frontotemporal dementia associated with inclusion body myopathy

  • Review
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

Abstract

Frontotemporal dementia with inclusion body myopathy and Paget’s disease of bone (IBMPFD) is a rare, autosomal dominant disorder caused by mutations in the gene valosin-containing protein (VCP). The CNS pathology is characterized by a novel pattern of ubiquitin pathology distinct from sporadic and familial frontotemporal lobar degeneration with ubiquitin-positive inclusions without VCP mutations. Yet, the ubiquitin-positive inclusions in IBMPFD also stain for TAR DNA binding protein, a feature that links this rare disease with the pathology associated with the majority of sporadic FTD as well as disease resulting from different genetic alterations. VCP, a member of the AAA-ATPase gene family, associates with a plethora of protein adaptors to perform a variety of cellular processes including Golgi assembly/disassembly and regulation of the ubiquitin–proteasome system. However, the mechanism whereby mutations in VCP lead to CNS, muscle, and bone disease is largely unknown. In this report, we review current literature on IBMPFD, focusing on the pathology of the disease and the biology of VCP with respect to IBMPFD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig 2

Similar content being viewed by others

References

  1. 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 (2001) Clinical delineation and localization to chromosome 9p13.3-p12 of a unique dominant disorder in four families: hereditary inclusion body myopathy, Paget’s disease of bone, and frontotemporal dementia. Mol Genet Metab 74:458–475

    Article  PubMed  CAS  Google Scholar 

  2. Kimonis VE, Kovach MJ, Waggoner B, Leal S, Salam A, Rimer L, Davis K, Khardori R, Gelber D (2000) Clinical and molecular studies in a unique family with autosomal dominant limb-girdle muscular dystrophy and Paget disease of bone. Genet Med 2:232–241

    PubMed  CAS  Google Scholar 

  3. Kimonis VE, Watts GD (2005) Autosomal dominant inclusion body myopathy, Paget disease of bone, and frontotemporal dementia. Alzheimer Dis Assoc Disord 19(Suppl 1):S44-S47

    Article  PubMed  Google Scholar 

  4. Lund, Manchester Groups (1994) Clinical and neuropathological criteria for frontotemporal dementia. J Neurol Neurosurg Psychiatry 57:416–418

    Article  Google Scholar 

  5. McKhann GM, Albert MS, Grossman M, Miller B, Dickson D, Trojanowski JQ (2001) Clinical and pathological diagnosis of frontotemporal dementia: report of the work group on frontotemporal dementia and Pick’s disease. Arch Neurol 58:1803–1809

    Article  PubMed  CAS  Google Scholar 

  6. 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 (2006) Novel ubiquitin neuropathology in frontotemporal dementia with valosin-containing protein gene mutations. J Neuropathol Exp Neurol 65:571–581

    PubMed  CAS  Google Scholar 

  7. Hubbers CU, Clemen CS, Kesper K, Boddrich A, Hofmann A, Kamarainen O, Tolksdorf K, Stumpf M, Reichelt J, Roth U, Krause S, Watts G, Kimonis V, Wattjes MP, Reimann J, Thal DR, Biermann K, Evert BO, Lochmuller H, Wanker EE, Schoser BG, Noegel AA, Schroder R (2007) Pathological consequences of VCP mutations on human striated muscle. Brain 130:381–393

    Article  PubMed  Google Scholar 

  8. Guyant-Marechal L, Laquerriere A, Duyckaerts C, Dumanchin C, Bou J, Dugny F, Le BI, Frebourg T, Hannequin D, Campion D (2006) Valosin-containing protein gene mutations: clinical and neuropathologic features. Neurology 67:644–651

    Article  PubMed  CAS  Google Scholar 

  9. Watts GD, Wymer J, Kovach MJ, Mehta SG, Mumm S, Darvish D, Pestronk A, Whyte MP, Kimonis VE (2004) Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. Nat Genet 36:377–381

    Article  PubMed  CAS  Google Scholar 

  10. Pirici D, Vandenberghe R, Rademakers R, Dermaut B, Cruts M, Vennekens K, Cuijt I, Lubke U, Ceuterick C, Martin JJ, Van BC, Kumar-Singh S (2006) Characterization of ubiquitinated intraneuronal inclusions in a novel Belgian frontotemporal lobar degeneration family. J Neuropathol Exp Neurol 65:289–301

    PubMed  Google Scholar 

  11. Haubenberger D, Bittner RE, Rauch-Shorny S, Zimprich F, Mannhalter C, Wagner L, Mineva I, Vass K, Auff E, Zimprich A (2005) Inclusion body myopathy and Paget disease is linked to a novel mutation in the VCP gene. Neurology 65:1304–1305

    Article  PubMed  CAS  Google Scholar 

  12. Schröder R, Watts GD, Mehta SG, Evert BO, Broich P, Fliessbach K, Pauls K, Hans VH, Kimonis V, Thal DR (2005) Mutant valosin-containing protein causes a novel type of frontotemporal dementia. Ann Neurol 57:457–461

    Article  PubMed  CAS  Google Scholar 

  13. Mehta SG, Watts GD, Adamson JL, Hutton M, Umberger G, Xiong S, Ramdeen S, Lovell MA, Kimonis VE, Smith CD (2007) APOE is a potential modifier gene in an autosomal dominant form of frontotemporal dementia (IBMPFD). Genet Med 9:9–13

    Article  PubMed  CAS  Google Scholar 

  14. Wang Q, Song C, Li CC (2004) Molecular perspectives on p97-VCP: progress in understanding its structure and diverse biological functions. J Struct Biol 146:44–57

    Article  PubMed  CAS  Google Scholar 

  15. Woodman PG (2003) p97, a protein coping with multiple identities. J Cell Sci 116:4283–4290

    Article  PubMed  CAS  Google Scholar 

  16. Zhang X, Shaw A, Bates PA, Newman RH, Gowen B, Orlova E, Gorman MA, Kondo H, Dokurno P, Lally J, Leonard G, Meyer H, Van HM, Freemont PS (2000) Structure of the AAA ATPase p97. Mol Cell 6:1473–1484

    Article  PubMed  CAS  Google Scholar 

  17. Rouiller I, DeLaBarre B, May AP, Weis WI, Brunger AT, Milligan RA, Wilson-Kubalek EM (2002) Conformational changes of the multifunction p97 AAA ATPase during its ATPase cycle. Nat Struct Biol 9:950–957

    Article  PubMed  CAS  Google Scholar 

  18. Dai RM, Li CC (2001) Valosin-containing protein is a multi-ubiquitin chain-targeting factor required in ubiquitin-proteasome degradation. Nat Cell Biol 3:740–744

    Article  PubMed  CAS  Google Scholar 

  19. Wojcik C, Yano M, DeMartino GN (2004) RNA interference of valosin-containing protein (VCP/p97) reveals multiple cellular roles linked to ubiquitin/proteasome-dependent proteolysis. J Cell Sci 117:281–292

    Article  PubMed  CAS  Google Scholar 

  20. Rouiller I, Butel VM, Latterich M, Milligan RA, Wilson-Kubalek EM (2000) A major conformational change in p97 AAA ATPase upon ATP binding. Mol Cell 6:1485–1490

    Article  PubMed  CAS  Google Scholar 

  21. Song C, Wang Q, Li CC (2003) ATPase activity of p97-valosin-containing protein (VCP). D2 mediates the major enzyme activity, and D1 contributes to the heat-induced activity. J Biol Chem 278:3648–3655

    Article  PubMed  CAS  Google Scholar 

  22. Wang Q, Song C, Yang X, Li CC (2003) D1 ring is stable and nucleotide-independent, whereas D2 ring undergoes major conformational changes during the ATPase cycle of p97-VCP. J Biol Chem 278:32784–32793

    Article  PubMed  CAS  Google Scholar 

  23. Wang Q, Song C, Li CC (2003) Hexamerization of p97-VCP is promoted by ATP binding to the D1 domain and required for ATPase and biological activities. Biochem Biophys Res Commun 300:253–260

    Article  PubMed  CAS  Google Scholar 

  24. Meyer HH, Shorter JG, Seemann J, Pappin D, Warren G (2000) A complex of mammalian ufd1 and npl4 links the AAA-ATPase, p97, to ubiquitin and nuclear transport pathways. EMBO J 19:2181–2192

    Article  PubMed  CAS  Google Scholar 

  25. Ye Y, Meyer HH, Rapoport TA (2003) Function of the p97-Ufd1-Npl4 complex in retrotranslocation from the ER to the cytosol: dual recognition of nonubiquitinated polypeptide segments and polyubiquitin chains. J Cell Biol 162:71–84

    Article  PubMed  CAS  Google Scholar 

  26. Egerton M, Samelson LE (1994) Biochemical characterization of valosin-containing protein, a protein tyrosine kinase substrate in hematopoietic cells. J Biol Chem 269:11435–11441

    PubMed  CAS  Google Scholar 

  27. Lavoie C, Chevet E, Roy L, Tonks NK, Fazel A, Posner BI, Paiement J, Bergeron JJ (2000) Tyrosine phosphorylation of p97 regulates transitional endoplasmic reticulum assembly in vitro. Proc Natl Acad Sci USA 97:13637–13642

    Article  PubMed  CAS  Google Scholar 

  28. Dreveny I, Pye VE, Beuron F, Briggs LC, Isaacson RL, Matthews SJ, McKeown C, Yuan X, Zhang X, Freemont PS (2004) p97 and close encounters of every kind: a brief review. Biochem Soc Trans 32:715–720

    Article  PubMed  CAS  Google Scholar 

  29. Uchiyama K, Jokitalo E, Kano F, Murata M, Zhang X, Canas B, Newman R, Rabouille C, Pappin D, Freemont P, Kondo H (2002) VCIP135, a novel essential factor for p97/p47-mediated membrane fusion, is required for Golgi and ER assembly in vivo. J Cell Biol 159:855–866

    Article  PubMed  CAS  Google Scholar 

  30. Uchiyama K, Jokitalo E, Lindman M, Jackman M, Kano F, Murata M, Zhang X, Kondo H (2003) The localization and phosphorylation of p47 are important for Golgi disassembly-assembly during the cell cycle. J Cell Biol 161:1067–1079

    Article  PubMed  CAS  Google Scholar 

  31. Uchiyama K, Totsukawa G, Puhka M, Kaneko Y, Jokitalo E, Dreveny I, Beuron F, Zhang X, Freemont P, Kondo H (2006) p37 is a p97 adaptor required for Golgi and ER biogenesis in interphase and at the end of mitosis. Dev Cell 11:803–816

    Article  PubMed  CAS  Google Scholar 

  32. Hartmann-Petersen R, Wallace M, Hofmann K, Koch G, Johnsen AH, Hendil KB, Gordon C (2004) The Ubx2 and Ubx3 cofactors direct Cdc48 activity to proteolytic and nonproteolytic ubiquitin-dependent processes. Curr Biol 14:824–828

    Article  PubMed  CAS  Google Scholar 

  33. Schuberth C, Richly H, Rumpf S, Buchberger A (2004) Shp1 and Ubx2 are adaptors of Cdc48 involved in ubiquitin-dependent protein degradation. EMBO Rep 5:818–824

    Article  PubMed  CAS  Google Scholar 

  34. Romisch K (2005) Endoplasmic reticulum-associated degradation. Annu Rev Cell Dev Biol 21:435–456

    Article  PubMed  CAS  Google Scholar 

  35. Braun S, Matuschewski K, Rape M, Thoms S, Jentsch S (2002) Role of the ubiquitin-selective CDC48 (UFD1/NPL4) chaperone (segregase) in ERAD of OLE1 and other substrates. EMBO J 21:615–621

    Article  PubMed  CAS  Google Scholar 

  36. Ye Y, Meyer HH, Rapoport TA (2001) The AAA ATPase Cdc48/p97 and its partners transport proteins from the ER into the cytosol. Nature 414:652–656

    Article  PubMed  CAS  Google Scholar 

  37. Rabinovich E, Kerem A, Frohlich KU, Diamant N, Bar-Nun S (2002) AAA-ATPase p97/Cdc48p, a cytosolic chaperone required for endoplasmic reticulum-associated protein degradation. Mol Cell Biol 22:626–634

    Article  PubMed  CAS  Google Scholar 

  38. Jarosch E, Taxis C, Volkwein C, Bordallo J, Finley D, Wolf DH, Sommer T (2002) Protein dislocation from the ER requires polyubiquitination and the AAA-ATPase Cdc48. Nat Cell Biol 4:134–139

    Article  PubMed  CAS  Google Scholar 

  39. Ye Y, Shibata Y, Yun C, Ron D, Rapoport TA (2004) A membrane protein complex mediates retro-translocation from the ER lumen into the cytosol. Nature 429:841–847

    Article  PubMed  CAS  Google Scholar 

  40. Rape M, Hoppe T, Gorr I, Kalocay M, Richly H, Jentsch S (2001) Mobilization of processed, membrane-tethered SPT23 transcription factor by CDC48 (UFD1/NPL4), a ubiquitin-selective chaperone. Cell 107:667–677

    Article  PubMed  CAS  Google Scholar 

  41. Meusser B, Hirsch C, Jarosch E, Sommer T (2005) ERAD: the long road to destruction. Nat Cell Biol 7:766–772

    Article  PubMed  CAS  Google Scholar 

  42. Forman MS, Farmer J, Johnson JK, Clark CM, Arnold SE, Coslett HB, Chatterjee A, Hurtig HI, Karlawish JH, Rosen HJ, Van DV, Lee VM, Miller BL, Trojanowski JQ, Grossman M (2006) Frontotemporal dementia: clinicopathological correlations. Ann Neurol 59:952–962

    Article  PubMed  Google Scholar 

  43. Lipton AM, White CL III, Bigio EH (2004) Frontotemporal lobar degeneration with motor neuron disease-type inclusions predominates in 76 cases of frontotemporal degeneration. Acta Neuropathol (Berl) 108:379–385

    Article  Google Scholar 

  44. Jackson M, Lennox G, Lowe J (1996) Motor neurone disease-inclusion dementia. Neurodegeneration 5:339–350

    Article  PubMed  CAS  Google Scholar 

  45. Okamoto K, Hirai S, Yamazaki T, Sun XY, Nakazato Y (1991) New ubiquitin-positive intraneuronal inclusions in the extra-motor cortices in patients with amyotrophic lateral sclerosis. Neurosci Lett 129:233–236

    Article  PubMed  CAS  Google Scholar 

  46. Wightman G, Anderson VE, Martin J, Swash M, Anderton BH, Neary D, Mann D, Luthert P, Leigh PN (1992) Hippocampal and neocortical ubiquitin-immunoreactive inclusions in amyotrophic lateral sclerosis with dementia. Neurosci Lett 139:269–274

    Article  PubMed  CAS  Google Scholar 

  47. Cooper PN, Jackson M, Lennox G, Lowe J, Mann DM (1995) Tau, ubiquitin, and alpha B-crystallin immunohistochemistry define the principal causes of degenerative frontotemporal dementia. Arch Neurol 52:1011–1015

    PubMed  CAS  Google Scholar 

  48. Mackenzie IR, Baborie A, Pickering-Brown S, Du PD, Jaros E, Perry RH, Neary D, Snowden JS, Mann DM (2006) Heterogeneity of ubiquitin pathology in frontotemporal lobar degeneration: classification and relation to clinical phenotype. Acta Neuropathol (Berl) 112:539–549

    Article  Google Scholar 

  49. Sampathu DM, Neumann M, Kwong LK, Chou TT, Micsenyi M, Truax A, Bruce J, Grossman M, Trojanowski JQ, Lee VM (2006) Pathological heterogeneity of frontotemporal lobar degeneration with ubiquitin-positive inclusions delineated by ubiquitin immunohistochemistry and novel monoclonal antibodies. Am J Pathol 169:1343–1352

    Article  PubMed  CAS  Google Scholar 

  50. Cairns NJ, Neumann M, Bigio EH, Holm IE, Troost D, Hatanpaa KJ, Foong C, White CL, III, Schneider JA, Kretzschmar HA, Carter D, Paulsmeyer K, Strider J, Gitcho M, Goate AM, Morris JC, Mishra M, Kwong LK, Stieber A, Xu Y, Forman MS, Trojanowski JQ, Lee VMY, Mackenzie IR (2007) TDP-43 in familial and sporadic frontotemporal lobar degeneration with ubiquitin inclusions. Am J Pathol (in press)

  51. Woulfe JM (2007) Abnormalities of the nucleus and nuclear inclusions in neurodegenerative disease: a work in progress. Neuropathol Appl Neurobiol 33:2–42

    PubMed  CAS  Google Scholar 

  52. Kumar-Singh S, Van Broeckhoven C (2007) Frontotemporal lobar degeneration: current concepts and advances. Brain Pathol 17:104–114

    Article  PubMed  CAS  Google Scholar 

  53. 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 (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130–133

    Article  PubMed  CAS  Google Scholar 

  54. Neumann M, Mackenzie IR, Cairns NJ, Boyer PJ, Markesbery WR, Smith CD, Taylor JP, Kretzschmar HA, Kimonis VE, Forman MS (2007) TDP-43 in the ubiquitin pathology of frontotemporal dementia with VCP gene mutations. J Neuropathol Exp Neurol 66:152–157

    Article  PubMed  Google Scholar 

  55. Hirabayashi M, Inoue K, Tanaka K, Nakadate K, Ohsawa Y, Kamei Y, Popiel AH, Sinohara A, Iwamatsu A, Kimura Y, Uchiyama Y, Hori S, Kakizuka A (2001) VCP/p97 in abnormal protein aggregates, cytoplasmic vacuoles, and cell death, phenotypes relevant to neurodegeneration. Cell Death Differ 8:977–984

    Article  PubMed  CAS  Google Scholar 

  56. Ishigaki S, Hishikawa N, Niwa J, Iemura S, Natsume T, Hori S, Kakizuka A, Tanaka K, Sobue G (2004) Physical and functional interaction between dorfin and valosin-containing protein that are colocalized in ubiquitylated inclusions in neurodegenerative disorders. J Biol Chem 279:51376–51385

    Article  PubMed  CAS  Google Scholar 

  57. Mizuno Y, Hori S, Kakizuka A, Okamoto K (2003) Vacuole-creating protein in neurodegenerative diseases in humans. Neurosci Lett 343:77–80

    Article  PubMed  CAS  Google Scholar 

  58. Yamanaka K, Okubo Y, Suzaki T, Ogura T (2004) Analysis of the two p97/VCP/Cdc48p proteins of Caenorhabditis elegans and their suppression of polyglutamine-induced protein aggregation. J Struct Biol 146:242–250

    Article  PubMed  CAS  Google Scholar 

  59. Higashiyama H, Hirose F, Yamaguchi M, Inoue YH, Fujikake N, Matsukage A, Kakizuka A (2002) Identification of ter94, Drosophila VCP, as a modulator of polyglutamine-induced neurodegeneration. Cell Death Differ 9:264–273

    Article  PubMed  CAS  Google Scholar 

  60. Boeddrich A, Gaumer S, Haacke A, Tzvetkov N, Albrecht M, Evert BO, Muller EC, Lurz R, Breuer P, Schugardt N, Plassmann S, Xu K, Warrick JM, Suopanki J, Wullner U, Frank R, Hartl UF, Bonini NM, Wanker EE (2006) An arginine/lysine-rich motif is crucial for VCP/p97-mediated modulation of ataxin-3 fibrillogenesis. EMBO J 25:1547–1558

    Article  PubMed  CAS  Google Scholar 

  61. Weihl CC, Dalal S, Pestronk A, Hanson PI (2006) Inclusion body myopathy-associated mutations in p97/VCP impair endoplasmic reticulum-associated degradation. Hum Mol Genet 15:189–199

    Article  PubMed  CAS  Google Scholar 

  62. Janiesch PC, Kim J, Mouysset J, Barikbin R, Lochmuller H, Cassata G, Krause S, Hoppe T (2007) The ubiquitin-selective chaperone CDC-48/p97 links myosin assembly to human myopathy. Nat Cell Biol 9:379–390

    Article  PubMed  CAS  Google Scholar 

  63. Weihl CC, Miller SE, Hanson PI, Pestronk A (2007) Transgenic expression of inclusion body myopathy associated mutant p97/VCP causes weakness and ubiquitinated protein inclusions in mice. Hum Mol Genet (in press)

Download references

Acknowledgments

This work was supported by grants from the NIH [AG10124 (MSF, JPT); NS053825 (JPT); and AG000255 (JBG, GR)], and the Penn Neuroscience Center (MSF, JBG, GR, JPT).

Author information

Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 422 Curie Blvd., 605B Stellar-Chance Building, Philadelphia, PA, 19104-6140, USA

    Jake B. Guinto & Mark S. Forman

  2. Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104, USA

    Gillian P. Ritson & J. Paul Taylor

  3. Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104, USA

    J. Paul Taylor & Mark S. Forman

Authors
  1. Jake B. Guinto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gillian P. Ritson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J. Paul Taylor
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mark S. Forman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mark S. Forman.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Guinto, J.B., Ritson, G.P., Taylor, J.P. et al. Valosin-containing protein and the pathogenesis of frontotemporal dementia associated with inclusion body myopathy. Acta Neuropathol 114, 55–61 (2007). https://doi.org/10.1007/s00401-007-0224-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-007-0224-7

Keywords

Search

Navigation