Multiple system degeneration with basophilic inclusions in Japanese ALS patients with FUS mutation (original) (raw)

Abstract

Mutations in the fused in sarcoma gene (FUS) were recently found in patients with familial amyotrophic lateral sclerosis (ALS). The present study aimed to clarify unique features of familial ALS caused by FUS mutation in the Japanese population. We carried out clinical, neuropathological, and genetic studies on a large Japanese pedigree with familial ALS. In six successive generations of this family, 16 individuals of both sexes were affected by progressive muscle atrophy and weakness, indicating an autosomal dominant trait. Neurological examination of six patients revealed an age at onset of 48.2 ± 8.1 years in fourth generation patients, while it was 31 and 20 years in fifth and sixth generation patients, respectively. Motor paralysis progressed rapidly in these patients, culminating in respiratory failure within 1 year. The missense mutation c.1561 C>T (p.R521C) was found in exon 15 of FUS in the four patients examined. Neuropathological study of one autopsied case with the FUS mutation revealed multiple system degeneration in addition to upper and lower motor neuron involvement: the globus pallidus, thalamus, substantia nigra, cerebellum, inferior olivary nucleus, solitary nucleus, intermediolateral horn, Clarke’s column, Onuf’s nucleus, central tegmental tract, medial lemniscus, medial longitudinal fasciculus, superior cerebellar peduncle, posterior column, and spinocerebellar tract were all degenerated. Argyrophilic and basophilic neuronal or glial cytoplasmic inclusions immunoreactive for FUS, GRP78/BiP, p62, and ubiquitin were detected in affected lesions. The FUS R521C mutation in this Japanese family caused familial ALS with pathological features of multiple system degeneration and neuronal basophilic inclusions.

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References

1. Baechtold H, Kuroda M, Sok J, Ron D, Lopez BS, Akhmedov AT (1999) Human 75-kDa DNA-pairing protein is identical to the pro-oncoprotein TLS/FUS and is able to promote D-loop formation. J Biol Chem 274:34337–34342
   Article PubMed CAS Google Scholar
2. Bertrand P, Akhmedov AT, Delacote F, Durrbach A, Lopez BS (1999) Human POMp75 is identified as the pro-oncoprotein TLS/FUS: both POMp75 and POMp100 DNA homologous pairing activities are associated to cell proliferation. Oncogene 18:4515–4521
   Article PubMed CAS Google Scholar
3. Crozat A, Aman P, Mandahl N, Ron D (1993) Fusion of CHOP to a novel RNA-binding protein in human myxoid liposarcoma. Nature 363:640–644
   Article PubMed CAS Google Scholar
4. Doi H, Okamura K, Bauer PO et al (2008) RNA-binding protein TLS is a major nuclear aggregate-interacting protein in Huntingtin exon 1 with expanded polyglutamine-expressing cells. J Biol Chem 283:6489–6500
   Article PubMed CAS Google Scholar
5. Frank S, Tolnay M (2009) Frontotemporal lobar degeneration: toward the end of conFUSion. Acta Neuropathol 118:629–631
   Article PubMed Google Scholar
6. Fujita K, Ito H, Nakano S, Kinoshita Y, Wate R, Kusaka H (2008) Immunohistochemical identification of messenger RNA-related proteins in basophilic inclusions of adult-onset atypical motor neuron disease. Acta Neuropathol 116:439–445
   Article PubMed CAS Google Scholar
7. Greenway MJ, Andersen PM, Russ C et al (2006) ANG mutations segregate with familial and ‘sporadic’ amyotrophic lateral sclerosis. Nat Genet 38:411–413
   Article PubMed CAS Google Scholar
8. Hayashi H, Kato S (1989) Total manifestations of amyotrophic lateral sclerosis. ALS in the totally locked-in state. J Neurol Sci 93:19–35
   Article PubMed CAS Google Scholar
9. Iwaki T, Kume-Iwaki A, Liem RK, Goldman JE (1989) Alpha B-crystallin is expressed in non-lenticular tissues and accumulates in Alexander’s disease brain. Cell 57:71–78
   Article PubMed CAS Google Scholar
10. Kabashi E, Valdmanis PN, Dion P et al (2008) TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat Genet 40:572–574
    Article PubMed CAS Google Scholar
11. Kikuchi H, Doh-ura K, Kawashima T, Kira J, Iwaki T (1999) Immunohistochemical analysis of spinal cord lesions in amyotrophic lateral sclerosis using microtubule-associated protein 2 (MAP2) antibodies. Acta Neuropathol 97:13–21
    Article PubMed CAS Google Scholar
12. Kusaka H, Matsumoto S, Imai T (1990) An adult-onset case of sporadic motor neuron disease with basophilic inclusions. Acta Neuropathol 80:660–665
    Article PubMed CAS Google Scholar
13. Kusaka H, Matsumoto S, Imai T (1993) Adult-onset motor neuron disease with basophilic intraneuronal inclusion bodies. Clin Neuropathol 12:215–218
    PubMed CAS Google Scholar
14. Kwiatkowski TJ Jr, Bosco DA, Leclerc AL et al (2009) Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science 323:1205–1208
    Article PubMed CAS Google Scholar
15. Lagier-Tourenne C, Cleveland DW (2009) Rethinking ALS: the FUS about TDP-43. Cell 136:1001–1004
    Article PubMed CAS Google Scholar
16. Matsumoto S, Kusaka H, Murakami N, Hashizume Y, Okazaki H, Hirano A (1992) Basophilic inclusions in sporadic juvenile amyotrophic lateral sclerosis: an immunocytochemical and ultrastructural study. Acta Neuropathol 83:579–583
    Article PubMed CAS Google Scholar
17. Mizutani T, Sakamaki S, Tsuchiya N et al (1992) Amyotrophic lateral sclerosis with ophthalmoplegia and multisystem degeneration in patients on long-term use of respirators. Acta Neuropathol 84:372–377
    Article PubMed CAS Google Scholar
18. Munoz DG, Neumann M, Kusaka H et al (2009) FUS pathology in basophilic inclusion body disease. Acta Neuropathol 118:617–627
    Article PubMed CAS Google Scholar
19. Munoz-Garcia D, Ludwin SK (1984) Classic and generalized variants of Pick’s disease: a clinicopathological, ultrastructural, and immunocytochemical comparative study. Ann Neurol 16:467–480
    Article PubMed CAS Google Scholar
20. Nelson JS, Prensky AL (1972) Sporadic juvenile amyotrophic lateral sclerosis. A clinicopathological study of a case with neuronal cytoplasmic inclusions containing RNA. Arch Neurol 27:300–306
    PubMed CAS Google Scholar
21. Neumann M, Rademakers R, Roeber S, Baker M, Kretzschmar HA, Mackenzie IR (2009) Frontotemporal lobar degeneration with FUS pathology. Brain 132:2922–2931
    Article PubMed Google Scholar
22. Neumann M, Roeber S, Kretzschmar HA, Rademakers R, Baker M, Mackenzie IR (2009) Abundant FUS-immunoreactive pathology in neuronal intermediate filament inclusion disease. Acta Neuropathol 118:605–616
    Article PubMed CAS Google Scholar
23. Nishihira Y, Tan CF, Hoshi Y et al (2009) Sporadic amyotrophic lateral sclerosis of long duration is associated with relatively mild TDP-43 pathology. Acta Neuropathol 117:45–53
    Article PubMed CAS Google Scholar
24. Nishihira Y, Tan CF, Onodera O et al (2008) Sporadic amyotrophic lateral sclerosis: two pathological patterns shown by analysis of distribution of TDP-43-immunoreactive neuronal and glial cytoplasmic inclusions. Acta Neuropathol 116:169–182
    Article PubMed CAS Google Scholar
25. Nonaka T, Kametani F, Arai T, Akiyama H, Hasegawa M (2009) Truncation and pathogenic mutations facilitate the formation of intracellular aggregates of TDP-43. Hum Mol Genet 18:3353–3364
    Article PubMed CAS Google Scholar
26. Oda M, Akagawa N, Tabuchi Y, Tanabe H (1978) A sporadic juvenile case of the amyotrophic lateral sclerosis with neuronal intracytoplasmic inclusions. Acta Neuropathol 44:211–216
    Article PubMed CAS Google Scholar
27. Piao YS, Wakabayashi K, Kakita A et al (2003) Neuropathology with clinical correlations of sporadic amyotrophic lateral sclerosis: 102 autopsy cases examined between 1962 and 2000. Brain Pathol 13:10–22
    Article PubMed Google Scholar
28. Rabbitts TH, Forster A, Larson R, Nathan P (1993) Fusion of the dominant negative transcription regulator CHOP with a novel gene FUS by translocation t(12;16) in malignant liposarcoma. Nat Genet 4:175–180
    Article PubMed CAS Google Scholar
29. Rosen DR, Siddique T, Patterson D et al (1993) Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362:59–62
    Article PubMed CAS Google Scholar
30. Shaw CE, Enayat ZE, Powell JF et al (1997) Familial amyotrophic lateral sclerosis. Molecular pathology of a patient with a SOD1 mutation. Neurology 49:1612–1616
    PubMed CAS Google Scholar
31. Sreedharan J, Blair IP, Tripathi VB et al (2008) TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319:1668–1672
    Article PubMed CAS Google Scholar
32. Tsuchiya K, Matsunaga T, Aoki M et al (2001) Familial amyotrophic lateral sclerosis with posterior column degeneration and basophilic inclusion bodies: a clinical, genetic and pathological study. Clin Neuropathol 20:53–59
    PubMed CAS Google Scholar
33. Vance C, Rogelj B, Hortobagyi T et al (2009) Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science 323:1208–1211
    Article PubMed CAS Google Scholar
34. Wang X, Arai S, Song X et al (2008) Induced ncRNAs allosterically modify RNA-binding proteins in cis to inhibit transcription. Nature 454:126–130
    Article PubMed CAS Google Scholar
35. Yang L, Embree LJ, Tsai S, Hickstein DD (1998) Oncoprotein TLS interacts with serine-arginine proteins involved in RNA splicing. J Biol Chem 273:27761–27764
    Article PubMed CAS Google Scholar
36. Yoshida M, Murakami N, Hashizume Y, Itoh E, Takahashi A (1992) A clinicopathological study of two respirator-aided long-survival cases of amyotrophic lateral sclerosis. Rinsho Shinkeigaku 32:259–265
    PubMed CAS Google Scholar

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Authors and Affiliations

1. Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
   Takahisa Tateishi, Toshihiro Hokonohara, Ryo Yamasaki, Hitoshi Kikuchi, Yuko Nagara, Yasumasa Ohyagi & Jun-ichi Kira
2. Department of Neuropathology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
   Hiroshi Tashiro & Toru Iwaki
3. Division of Human Molecular Genetics, Research Center for Genetic Information, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
   Toshihiro Hokonohara, Akiko Iwaki & Yasuyuki Fukumaki
4. Division of Respirology, Neurology and Rheumatology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
   Shiro Miura
5. Department of Neurology, Neuro-Muscular Center, National Omuta Hospital, Omuta, Japan
   Hirokazu Furuya
6. Laboratory for Structural Neuropathology, RIKEN Brain Science Institute, Wako, Saitama, Japan
   Nobuyuki Nukina

Authors

1. Takahisa Tateishi
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2. Toshihiro Hokonohara
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3. Ryo Yamasaki
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4. Shiro Miura
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5. Hitoshi Kikuchi
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6. Akiko Iwaki
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7. Hiroshi Tashiro
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8. Hirokazu Furuya
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9. Yuko Nagara
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10. Yasumasa Ohyagi
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11. Nobuyuki Nukina
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12. Toru Iwaki
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13. Yasuyuki Fukumaki
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14. Jun-ichi Kira
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Correspondence toJun-ichi Kira.

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Tateishi, T., Hokonohara, T., Yamasaki, R. et al. Multiple system degeneration with basophilic inclusions in Japanese ALS patients with FUS mutation.Acta Neuropathol 119, 355–364 (2010). https://doi.org/10.1007/s00401-009-0621-1

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• Received: 07 August 2009
• Revised: 26 November 2009
• Accepted: 26 November 2009
• Published: 05 December 2009
• Issue Date: March 2010
• DOI: https://doi.org/10.1007/s00401-009-0621-1

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