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Accumulation of TDP-43 and α-actin in an amyotrophic lateral sclerosis patient with the K17I ANG mutation

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Abstract

A K17I mutation in the ANG gene encoding angiogenin has been identified in a case that we previously published as ALS with neuronal intranuclear protein inclusions (Seilhean et al. in Acta Neuropathol 108:81–87, 2004). These inclusions were immunoreactive for smooth muscle α-actin but not for angiogenin. Moreover, they were not labeled by anti-TDP-43 antibodies, while numerous cytoplasmic inclusions immunoreactive for ubiquitin, p62 and TDP-43 were detected in both oligodendrocytes and neurons in various regions of the central nervous system. In addition, expression of smooth muscle α-actin was increased in the liver where severe steatosis was observed. This is the first neuropathological description of a case with an ANG mutation. Angiogenin is known to interact with actin. Like other proteins involved in ALS pathogenesis, such as senataxin, TDP-43 and FUS/TLS, it plays a role in RNA maturation.

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References

  1. Baker M, Mackenzie I, Pickering-Brown S et al (2006) Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 442:916–919

    Article  PubMed  CAS  Google Scholar 

  2. Bowman A, Yoo S, Dantuma N, Zoghbi H (2005) Neuronal dysfunction in a polyglutamine disease model occurs in the absence of ubiquitin-proteasome system impairment and inversely correlates with the degree of nuclear inclusion formation. Hum Mol Genet 14:679–691

    Article  PubMed  CAS  Google Scholar 

  3. Braak H, Braak E (1989) Cortical and subcortical argyrophilic grains characterize a disease associated with adult onset dementia. Neuropathol Appl Neurobiol 15:13–26

    Article  PubMed  CAS  Google Scholar 

  4. Cairns N, Neumann M, Bigio E et al (2007) TDP-43 in familial and sporadic frontotemporal lobar degeneration with ubiquitin inclusions. Am J Pathol 171:227–240

    Article  PubMed  CAS  Google Scholar 

  5. Cao Y (2007) Angiogenesis modulates adipogenesis and obesity. J Clin Invest 117:2362–2368

    Article  PubMed  CAS  Google Scholar 

  6. Chen Y, Bennett C, Huynh H et al (2004) DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4). Am J Hum Genet 74:1128–1135

    Article  PubMed  CAS  Google Scholar 

  7. Crabtree B, Thiyagarajan N, Prior S et al (2007) Characterization of human angiogenin variants implicated in amyotrophic lateral sclerosis. Biochemistry 46:11810–11818

    Article  PubMed  CAS  Google Scholar 

  8. Daoud H, Valdmanis P, Kabashi E et al (2008) Contribution of TARDBP mutations to sporadic amyotrophic lateral sclerosis. J Med Genet (Epub ahead of print)

  9. Davidson Y, Kelley T, Mackenzie I et al (2007) Ubiquitinated pathological lesions in frontotemporal lobar degeneration contain the TAR DNA-binding protein, TDP-43. Acta Neuropathol 113:521–533

    Article  PubMed  CAS  Google Scholar 

  10. Dickson D, Josephs K, Amador-Ortiz C (2007) TDP-43 in differential diagnosis of motor neuron disorders. Acta Neuropathol 114:71–79

    Article  PubMed  CAS  Google Scholar 

  11. Dunah A, Wyszynski M, Martin D, Sheng M, Standaert D (2000) α-Actinin-2 in rat striatum: localization and interaction with NMDA glutamate receptor subunits. Brain Res Mol Brain Res 79:77–87

    Article  PubMed  CAS  Google Scholar 

  12. Dupuis L, Corcia P, Fergani A et al (2008) Dyslipidemia is a protective factor in amyotrophic lateral sclerosis. Neurology 70:988–989

    Article  Google Scholar 

  13. Etoh T, Shibuta K, Barnard G, Keitano S, Mori M (2000) Angiogenin expression in human colorectal cancer: the role of focal macrophage infiltration. Clin Cancer Res 6:3545–3551

    PubMed  CAS  Google Scholar 

  14. Fernández-Santiago R, Hoenig S, Lichtner P et al (2009) Identification of novel Angiogenin (ANG) gene missense variants in German patients with amyotrophic lateral sclerosis. J Neurol (Epub ahead of print)

  15. Fett J, Strydom D, Lobb R et al (1985) Isolation and characterization of angiogenin, an angiogenic protein from human carcinoma cells. Biochemistry 24:5480–5486

    Article  PubMed  CAS  Google Scholar 

  16. Gitcho M, Baloh R, Chakraverty S et al (2008) TDP-43 A315T mutation in familial motor neuron disease. Ann Neurol 63:535–538

    Article  PubMed  CAS  Google Scholar 

  17. Greenway M, Alexander M, Ennis S et al (2004) A novel candidate region for ALS on chromosome 14q11.2. Neurology 63:1936–1938

    PubMed  CAS  Google Scholar 

  18. Greenway M, Andersen P, Russ C et al (2006) ANG mutations segregate with familial and “sporadic” amyotrophic lateral sclerosis. Nat Genet 30:411–413

    Article  Google Scholar 

  19. Hatzi E, Badet J (1999) Expression of receptors for human angiogenin in vascular smooth muscle cells. Eur J Biochem 260:825–832

    Article  PubMed  CAS  Google Scholar 

  20. Hetman M, Gozdz A (2004) Role of extracellular signal regulated kinases 1 and 2 in neuronal survival. Eur J Biochem 271:2050–2055

    Article  PubMed  CAS  Google Scholar 

  21. Hiji M, Takahashi T, Fukuba H, Yamashita H, Kohriyama T, Matsumoto M (2008) White matter lesions in the brain with frontotemporal lobar degeneration with motor neuron disease: TDP-43-immunopositive inclusions co-localize with p62, but not ubiquitin. Acta Neuropathol 116:183–191

    Article  PubMed  CAS  Google Scholar 

  22. Hisai H, Kato J, Kobune M et al (2003) Increased expression of angiogenin in hepatocellular carcinoma in correlation with tumor vascularity. Clin Cancer Res 9:4852–4859

    PubMed  CAS  Google Scholar 

  23. Hu G, Chang S, Riordan J, Vallee B (1991) An angiogenin-binding protein from endothelial cells. Proc Natl Acad Sci USA 88:2227–2231

    Article  PubMed  CAS  Google Scholar 

  24. Hu G, Riordan J, Vallee B (1994) Angiogenin promotes invasiveness of cultured endothelial cells by stimulation of cell-associated proteolytic activities. Proc Natl Acad Sci USA 91:12096–12100

    Article  PubMed  CAS  Google Scholar 

  25. Hu G, Riordan J, Vallee B (1997) A putative angiogenin receptor in angiogenin-responsive human endothelial cells. Proc Natl Acad Sci USA 94:2204–2209

    Article  PubMed  CAS  Google Scholar 

  26. Hu G, Strydom D, Fett J, Riordan J, Vallee B (1993) Actin is a binding protein for angiogenin. Proc Natl Acad Sci USA 90:1217–1221

    Article  PubMed  CAS  Google Scholar 

  27. Hu H, Gao X, Sun Y, Zhou J, Yang M, Xu Z (2005) α-Actinin-2, a cytoskeletal protein, binds to angiogenin. Biochem Biophys Res Commun 329:661–667

    Article  PubMed  CAS  Google Scholar 

  28. Jimi S, Ito K, Kohno K, Kuwano M, Itagaki Y, Ishikawa H (1995) Modulation by bovine angiogenin of tubular morphogenesis and expression of plasminogen activator in bovine endothelial cells. Biochem Biophys Res Commun 211:476–483

    Article  PubMed  CAS  Google Scholar 

  29. Josephs K, Lin W, Ahmed Z, Stroh D, Graff-Radford N, Dickson D (2008) Frontotemporal lobar degeneration with ubiquitin-positive, but TDP-43-negative inclusions. Acta Neuropathol 116:159–167

    Article  PubMed  CAS  Google Scholar 

  30. Kabashi E, Valdmanis P, 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 

  31. Kieran D, Sebastia J, Greenway M et al (2008) Control of motoneuron survival by angiogenin. J Neurosci 28:14056–14061

    Article  PubMed  CAS  Google Scholar 

  32. Kim H, Kang D, Kim H, Kang S, Chang S (2007) Angiogenin-induced protein kinase B/Akt activation is necessary for angiogenesis but is independent of nuclear translocation of angiogenin in HUVE cells. Biochem Biophys Res Commun 352:509–513

    Article  PubMed  CAS  Google Scholar 

  33. Komori T (1999) Tau-positive glial inclusions in progressive supranuclear palsy, corticobasal degeneration and Pick’s disease. Brain Pathol 9:663–679

    PubMed  CAS  Google Scholar 

  34. Kovacs G, Majtenyi K, Spina S et al (2008) White matter tauopathy with globular glial inclusions: a distinct sporadic frontotemporal lobar degeneration. J Neuropathol Exp Neurol 67:963–975

    Article  PubMed  Google Scholar 

  35. Kwiatkowski T, Bosco D, Leclerc A 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 

  36. Lagier-Tourenne C, Cleveland D (2009) Rethinking ALS: the FUS about TDP-43. Cell 136:1001–1004

    Article  PubMed  CAS  Google Scholar 

  37. Landers J, Leclerc A, Shi L et al (2008) New VAPB deletion variant and exclusion of VAPB mutations in familial ALS. Neurology 70:1179–1185

    Article  PubMed  CAS  Google Scholar 

  38. Lin X, Yue P, Chen Z, Schonfeld G (2005) Hepatic triglyceride contents are genetically determined in mice: results of a strain survey. Am J Physiol Gastrointest Liver Physiol 288:G1179–G1189

    Article  PubMed  CAS  Google Scholar 

  39. Mackenzie I, Baker M, Pickering-Brown S et al (2006) The neuropathology of frontotemporal lobar degeneration caused by mutations in the progranulin gene. Brain 129:3081–3090

    Article  PubMed  Google Scholar 

  40. Maquat L (2004) Nonsense-mediated mRNA decay: splicing, translation and mRNP dynamics. Nat Rev Mol Cell Biol 5:89–99

    Article  PubMed  CAS  Google Scholar 

  41. Moroianu J, Fett J, Riordan J, Vallee B (1993) Actin is a surface component of calf pulmonary artery endothelial cells in culture. Proc Natl Acad Sci USA 90:3815–3819

    Article  PubMed  CAS  Google Scholar 

  42. Moroianu J, Riordan J (1994) Nuclear translocation of angiogenin in proliferating endothelial cells is essential to its angiogenic activity. Proc Natl Acad Sci USA 91:1677–1681

    Article  PubMed  CAS  Google Scholar 

  43. Nishihira Y, Tan C, 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 

  44. Nishimura A, Mitne-Neto M, Silva H et al (2004) A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis. Am J Hum Genet 75:822–831

    Article  PubMed  CAS  Google Scholar 

  45. Oosthuyse B, Moons L, Storkebaum E et al (2001) Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration. Nat Genet 28:131–138

    Article  PubMed  CAS  Google Scholar 

  46. Papp M, Kahn J, Lantos P (1989) Glial cytoplasmic inclusions in the CNS of patients with multiple system atrophy (striatonigral degeneration, olivopontocerebellar atrophy and Shy-Drager syndrome). J Neurol Sci 94:79–100

    Article  PubMed  CAS  Google Scholar 

  47. Rademakers R, Eriksen J, Baker M et al (2008) Common variation in the miR-659 binding-site of GRN is a major risk factor for TDP43-positive frontotemporal dementia. Hum Mol Genet 17:3631–3642

    Article  PubMed  CAS  Google Scholar 

  48. Roark E, Keene D, Haudenschild C, Godyna S, Little C, Argraves W (1995) The association of human fibulin-1 with elastic fibers: an immunohistological, ultrastructural, and RNA study. J Histochem Cytochem 43:401–411

    PubMed  CAS  Google Scholar 

  49. Roeber S, Mackenzie I, Kretzschmar H, Neumann M (2008) TDP-43-negative FTLD-U is a significant new clinico-pathological subtype of FTLD. Acta Neuropathol 116:147–157

    Article  PubMed  CAS  Google Scholar 

  50. Rosen D, 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 

  51. Rosenmund C, Westbrook G (1993) Calcium-induced actin depolymerization reduces NMDA channel activity. Neuron 10:805–814

    Article  PubMed  CAS  Google Scholar 

  52. Rutherford N, Zhang Y, Baker M et al (2008) Novel mutations in TARDBP (TDP-43) in patients with familial amyotrophic lateral sclerosis. PLoS Genet 4:e1000193

    Article  PubMed  Google Scholar 

  53. Seilhean D, Takahashi J, El Achimi K et al (2004) Amyotrophic lateral sclerosis with neuronal intranuclear protein inclusions. Acta Neuropathol 108:81–87

    Article  PubMed  Google Scholar 

  54. Shapiro R, Strydom D, Olson K, Vallee B (1987) Isolation of angiogenin from normal human plasma. Biochemistry 26:5141–5146

    Article  PubMed  CAS  Google Scholar 

  55. Shapiro R, Vallee B (1989) Site-directed mutagenesis of histidine-13 and histidine-114 of human angiogenin. Alanine derivatives inhibit angiogenin-induced angiogenesis. Biochemistry 28:7401–7408

    Article  PubMed  CAS  Google Scholar 

  56. Sjöblom B, Salmazo A, Djinovic-Carugo K (2008) α-actinin structure and regulation. Cell Mol Life Sci 65:2688–2701

    Article  PubMed  Google Scholar 

  57. Sreedharan J, Blair I, Tripathi V et al (2008) TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319:1668–1672

    Article  PubMed  CAS  Google Scholar 

  58. Subramanian V, Feng Y (2007) A new role for angiogenin in neurite growth and pathfinding: implications for amyotrophic lateral sclerosis. Hum Mol Genet 16:1445–1453

    Article  PubMed  CAS  Google Scholar 

  59. Tsuji T, Sun Y, Kishimoto K et al (2005) Angiogenin is translocated to the nucleus of HeLa cells and is involved in ribosomal RNA transcription and cell proliferation. Cancer Res 65:1352–1360

    Article  PubMed  CAS  Google Scholar 

  60. Van Deerlin V, Leverenz J, Bekris L et al (2008) TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis. Lancet Neurol 7:409–416

    Article  PubMed  Google Scholar 

  61. 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 

  62. Vandekerckhove J, Weber K (1978) At least six different actins are expressed in a higher mammal: an analysis based on the amino acid sequence of the amino-terminal tryptic peptide. J Mol Biol 126:783–802

    Article  PubMed  CAS  Google Scholar 

  63. Weiner H, Weiner L, Swain J (1987) Tissue distribution and developmental expression of the messenger RNA encoding angiogenin. Science 237:280–282

    Article  PubMed  CAS  Google Scholar 

  64. Wu D, Yu W, Kishikawa H et al (2007) Angiogenin loss-of-function mutations in amyotrophic lateral sclerosis. Ann Neurol 62:609–617

    Article  PubMed  CAS  Google Scholar 

  65. Wyszynski M, Lin J, Rao A et al (1997) Competitive binding of α-actinin and calmodulin to the NMDA receptor. Nature 385:439–442

    Article  PubMed  CAS  Google Scholar 

  66. Yamasaki S, Ivanov P, Hu G, Anderson P (2009) Angiogenin cleaves tRNA and promotes stress-induced translational repression. J Cell Biol 185:35–42

    Google Scholar 

  67. Yang Y, Hentati A, Deng H-X et al (2001) The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis. Nat Genet 29:160–165

    Article  PubMed  CAS  Google Scholar 

  68. Yokoseki A, Shiga A, Tan C et al (2008) TDP-43 mutation in familial amyotrophic lateral sclerosis. Ann Neurol 63:538–542

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

Many thanks to the technical staff of Escourolle laboratory; to Drs Odile Dubourg, Eva Comperat, and Frédéric Charlotte who provided some of the control cases; to the Institute of Myology and Laboratory of Pathology, who provided some of the antibodies and to Pr. Umberto De Girolami for helpful advice on the manuscript.

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Authors and Affiliations

  1. Département de Neuropathologie, UPMC Université Paris 06, AP-HP, Assistance Publique Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière, INSERM UMR-S 546 (DS) and UMR-S 679 (CD), 47-83 boulevard de l’Hôpital, 75651, Paris cedex 13, France

    Danielle Seilhean & Charles Duyckaerts

  2. Département de Génétique et Cytogénétique, AP-HP, Assistance Publique Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière, U.F. de Neurogénétique Moléculaire et Cellulaire, Paris, France

    Cécile Cazeneuve & Odile Russaouen

  3. Département de Neuropathologie, AP-HP, Assistance Publique Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière, Paris, France

    Valérie Thuriès

  4. Laboratoire de Génétique Moléculaire de la Neurotransmission et des Processus Neurodégénératifs, CNRS UMR 7091, UPMC Université Paris 06, Groupe Hospitalier Pitié-Salpêtrière, Paris, France

    Stéphanie Millecamps

  5. AP-HP, Assistance Publique Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière, Fédération de Neurologie, Centre Référent Maladie Rares SLA, Paris, France

    François Salachas

  6. UPMC Université Paris 06, AP-HP, Assistance Publique Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière, Fédération de Neurologie, Centre Référent Maladie Rares SLA, Paris, France

    Vincent Meininger

  7. Département de Génétique et Cytogénétique, UPMC Université Paris 06, INSERM, UMR-S 679 Neurologie and Thérapeutique Expérimentale, AP-HP, Assistance Publique Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière, U.F. de Neurogénétique Moléculaire et Cellulaire, Paris, France

    Eric LeGuern

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  1. Danielle Seilhean
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  2. Cécile Cazeneuve
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  3. Valérie Thuriès
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  9. Charles Duyckaerts
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Correspondence to Danielle Seilhean.

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Seilhean, D., Cazeneuve, C., Thuriès, V. et al. Accumulation of TDP-43 and α-actin in an amyotrophic lateral sclerosis patient with the K17I ANG mutation. Acta Neuropathol 118, 561–573 (2009). https://doi.org/10.1007/s00401-009-0545-9

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