Acta Neuropathologica

, Volume 122, Issue 2, pp 223–229

Clinicopathologic study on an ALS family with a heterozygous E478G optineurin mutation

  • Hidefumi Ito
  • Masataka Nakamura
  • Osamu Komure
  • Takashi Ayaki
  • Reika Wate
  • Hirofumi Maruyama
  • Yoshimi Nakamura
  • Kengo Fujita
  • Satoshi Kaneko
  • Yoko Okamoto
  • Masafumi Ihara
  • Tetsuro Konishi
  • Kazumasa Ogasawara
  • Asao Hirano
  • Hirofumi Kusaka
  • Ryuji Kaji
  • Ryosuke Takahashi
  • Hideshi Kawakami
Original Paper

Abstract

We investigated a family manifesting amyotrophic lateral sclerosis (ALS) with a heterozygous E478G mutation in the optineurin (OPTN) gene. Clinically, slow deterioration of motor function, mood and personality changes, temporal lobe atrophy on neuroimaging, and bizarre finger deformity were noted. Neuropathologically, TAR DNA-binding protein 43 (TDP-43)-positive neuronal intracytoplasmic inclusions were observed in the spinal and medullary motor neurons. In these cells, the immunoreactivity of nuclear TDP-43 was reduced. Consecutive sections revealed that the inclusions were also reactive with anti-ubiquitin and anti-p62 antibodies, but noticeably negative for OPTN. In addition, TDP-43/p62-positive glial cytoplasmic inclusions (GCIs) were scattered throughout the spinal cord and the medullary motor nuclei. Furthermore, Golgi fragmentation was identified in 70% of the anterior horn cells (AHCs). The presence of AHCs with preserved nuclear TDP-43 and a fragmented Golgi apparatus, which are unrecognizable in sporadic ALS, indicates that patients with the E4787G OPTN mutation would manifest Golgi fragmentation before loss of nuclear TDP-43. In the neocortex, GCIs were sparsely scattered among the primary motor and temporal cortices, but no neuronal TDP-43-positive inclusions were detected. In the amygdala and the ambient gyrus, argyrophilic grains and ballooned neurons were seen. The thorough neuropathologic investigations performed in this work demonstrated that OPTN-positive inclusion bodies, if any, were not prominent. We postulate that optineurinopathy is closely linked with TDP-proteinopathy and speculate that this heterozygous E478G mutation would cause ALS by acting through a dominant-negative mechanism.

Keywords

Amyotrophic lateral sclerosis Optineurin TDP-43 Golgi fragmentation 

Supplementary material

401_2011_842_MOESM1_ESM.pdf (210 kb)
ESM1 (PDF 211 kb)

References

  1. 1.
    Albagha OM, Visconti MR, Alonso N et al (2010) Genome-wide association study identifies variants at CSF1, OPTN and TNFRSF11A as genetic risk factors for Paget’s disease of bone. Nat Genet 42:520–524PubMedCrossRefGoogle Scholar
  2. 2.
    Baker M, Mackenzie IR, Pickering-Brown SM et al (2006) Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 442:916–919PubMedCrossRefGoogle Scholar
  3. 3.
    Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82:239–259PubMedCrossRefGoogle Scholar
  4. 4.
    Cruts M, Gijselinck I, van der Zee J et al (2006) Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature 442:920–924PubMedCrossRefGoogle Scholar
  5. 5.
    Ferrer I, Santpere G, van Leeuwen FW (2008) Argyrophilic grain disease. Brain 131:1416–1432PubMedCrossRefGoogle Scholar
  6. 6.
    Fujishiro H, Uchikado H, Arai T et al (2009) Accumulation of phosphorylated TDP-43 in brains of patients with argyrophilic grain disease. Acta Neuropathol 117:151–158PubMedCrossRefGoogle Scholar
  7. 7.
    Fujita Y, Mizuno Y, Takatama M, Okamoto K (2008) Anterior horn cells with abnormal TDP-43 immunoreactivities show fragmentation of the Golgi apparatus in ALS. J Neurol Sci 269:30–34PubMedCrossRefGoogle Scholar
  8. 8.
    Gonatas NK, Stieber A, Mourelatos Z et al (1992) Fragmentation of the Golgi apparatus of motor neurons in amyotrophic lateral sclerosis. Am J Pathol 140:731–737PubMedGoogle Scholar
  9. 9.
    Hortobágyi T, Troakes C, Nishimura AL et al (2011) Optineurin inclusions occur in a minority of TDP-43 positive ALS and FTLD-TDP cases and are rarely observed in other neurodegenerative disorders. Acta Neuropathol 121:519–527PubMedCrossRefGoogle Scholar
  10. 10.
    Ito H, Fujita K, Nakamura M et al (2011) Optineurin is co-localized with FUS in basophilic inclusions of ALS with FUS mutation and in basophilic inclusion body disease. Acta Neuropathol 121:555–557PubMedCrossRefGoogle Scholar
  11. 11.
    Johnson JO, Mandrioli J, Benatar M et al (2010) Exome sequencing reveals VCP mutations as a cause of familial ALS. Neuron 68:857–864PubMedCrossRefGoogle Scholar
  12. 12.
    Josephs KA, Ahmed Z, Katsuse O et al (2007) Neuropathologic features of frontotemporal lobar degeneration with ubiquitin-positive inclusions with progranulin gene (PGRN) mutations. J Neuropathol Exp Neurol 66:142–151PubMedCrossRefGoogle Scholar
  13. 13.
    Mackenzie IR, Rademakers R, Neumann M (2010) TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia. Lancet Neurol 9:995–1007PubMedCrossRefGoogle Scholar
  14. 14.
    Martinez-Lage P, Munoz DG (1997) Prevalence and disease associations of argyrophilic grains of Braak. J Neuropathol Exp Neurol 56:157–164PubMedCrossRefGoogle Scholar
  15. 15.
    Maruyama H, Morino H, Ito H et al (2010) Mutations of optineurin in amyotrophic lateral sclerosis. Nature 465:223–226PubMedCrossRefGoogle Scholar
  16. 16.
    Neumann M, Mackenzie IR, Cairns NJ et al (2007) TDP-43 in the ubiquitin pathology of frontotemporal dementia with VCP gene mutations. J Neuropathol Exp Neurol 66:152–157PubMedCrossRefGoogle Scholar
  17. 17.
    Osawa T, Mizuno Y, Fujita Y, Takatama M, Nakazato Y, Okamoto K (2011) Optineurin in neurodegenerative diseases. Neuropathology. doi:10.1111/j.1440-1789.2011.01199.x
  18. 18.
    Rezaie T, Child A, Hitchings R et al (2002) Adult-onset primary open-angle glaucoma caused by mutations in optineurin. Science 295:1077–1079PubMedCrossRefGoogle Scholar
  19. 19.
    Sahlender DA, Roberts RC, Arden SD et al (2005) Optineurin links myosin VI to the Golgi complex and is involved in Golgi organization and exocytosis. J Cell Biol 169:285–295PubMedCrossRefGoogle Scholar
  20. 20.
    Saito Y, Ruberu NN, Sawabe M et al (2004) Staging of argyrophilic grains: an age-associated tauopathy. J Neuropathol Exp Neurol 63:911–918PubMedGoogle Scholar
  21. 21.
    Seilhean D, Cazeneuve C, Thuriès V et al (2009) Accumulation of TDP-43 and alpha-actin in an amyotrophic lateral sclerosis patient with the K17I ANG mutation. Acta Neuropathol 118:561–573PubMedCrossRefGoogle Scholar
  22. 22.
    Van Deerlin VM, Leverenz JB, Bekris LM et al (2008) TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis. Lancet Neurol 7:409–416PubMedCrossRefGoogle Scholar
  23. 23.
    Watts GD, Wymer J, Kovach MJ et al (2004) Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. Nat Genet 36:377–381PubMedCrossRefGoogle Scholar
  24. 24.
    Ying H, Shen X, Park B, Yue BY (2010) Posttranslational modifications, localization, and protein interactions of optineurin, the product of a glaucoma gene. PLoS One 5:e9168PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Hidefumi Ito
    • 1
  • Masataka Nakamura
    • 2
  • Osamu Komure
    • 3
  • Takashi Ayaki
    • 1
  • Reika Wate
    • 2
  • Hirofumi Maruyama
    • 4
  • Yoshimi Nakamura
    • 2
  • Kengo Fujita
    • 2
  • Satoshi Kaneko
    • 2
  • Yoko Okamoto
    • 1
  • Masafumi Ihara
    • 1
  • Tetsuro Konishi
    • 5
  • Kazumasa Ogasawara
    • 6
  • Asao Hirano
    • 7
  • Hirofumi Kusaka
    • 2
  • Ryuji Kaji
    • 8
  • Ryosuke Takahashi
    • 1
  • Hideshi Kawakami
    • 4
  1. 1.Department of NeurologyKyoto University Graduate School of MedicineKyotoJapan
  2. 2.Department of NeurologyKansai Medical UniversityOsakaJapan
  3. 3.Shin-ai HospitalOsakaJapan
  4. 4.Department of EpidemiologyResearch Institute for Radiation Biology and Medicine, Hiroshima UniversityHiroshimaJapan
  5. 5.National Hospital Organization Utano HospitalKyotoJapan
  6. 6.Department of Pathology, School of MedicineShiga University of Medical ScienceShigaJapan
  7. 7.Division of Neuropathology, Department of PathologyMontefiore Medical CenterNew YorkUSA
  8. 8.Department of Clinical NeuroscienceUniversity of Tokushima Graduate SchoolTokushimaJapan

Personalised recommendations