Acta Neuropathologica

, Volume 125, Issue 3, pp 413–423 | Cite as

hnRNP A3 binds to GGGGCC repeats and is a constituent of p62-positive/TDP43-negative inclusions in the hippocampus of patients with C9orf72 mutations

  • Kohji Mori
  • Sven Lammich
  • Ian R. A. Mackenzie
  • Ignasi Forné
  • Sonja Zilow
  • Hans Kretzschmar
  • Dieter Edbauer
  • Jonathan Janssens
  • Gernot Kleinberger
  • Marc Cruts
  • Jochen Herms
  • Manuela Neumann
  • Christine Van Broeckhoven
  • Thomas Arzberger
  • Christian Haass
Original Paper


Genetic analysis revealed the hexanucleotide repeat expansion GGGGCC within the regulatory region of the gene C9orf72 as the most common cause of familial amyotrophic lateral sclerosis and the second most common cause of frontotemporal lobar degeneration. Since repeat expansions might cause RNA toxicity via sequestration of RNA-binding proteins, we searched for proteins capable of binding to GGGGCC repeats. In vitro-transcribed biotinylated RNA containing hexanucleotide GGGGCC or, as control, AAAACC repeats were incubated with nuclear protein extracts. Using stringent filtering protocols 20 RNA-binding proteins with a variety of different functions in RNA metabolism, translation and transport were identified. A subset of these proteins was further investigated by immunohistochemistry in human autopsy brains. This revealed that hnRNP A3 formed neuronal cytoplasmic and intranuclear inclusions in the hippocampus of patients with C9orf72 repeat extensions. Confocal microcopy showed that these inclusions belong to the group of the so far enigmatic p62-positive/TDP-43 negative inclusions characteristically seen in autopsy cases of diseased C9orf72 repeat expansion carriers. Thus, we have identified one protein component of these pathognomonic inclusions.


ALS C9orf72 FTLD hnRNP A3 Neurodegeneration TDP-43 

Supplementary material

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Supplementary material 1 (XLSX 62 kb)
401_2013_1088_MOESM2_ESM.pdf (536 kb)
Supplementary material 2 (PDF 536 kb)
401_2013_1088_MOESM3_ESM.docx (33 kb)
Supplementary material 3 (DOCX 33 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Kohji Mori
    • 1
  • Sven Lammich
    • 1
  • Ian R. A. Mackenzie
    • 2
  • Ignasi Forné
    • 3
  • Sonja Zilow
    • 1
  • Hans Kretzschmar
    • 4
  • Dieter Edbauer
    • 5
  • Jonathan Janssens
    • 6
    • 7
  • Gernot Kleinberger
    • 1
    • 5
    • 6
    • 7
  • Marc Cruts
    • 6
    • 7
  • Jochen Herms
    • 5
    • 8
  • Manuela Neumann
    • 9
    • 10
  • Christine Van Broeckhoven
    • 6
    • 7
  • Thomas Arzberger
    • 4
  • Christian Haass
    • 1
    • 5
    • 8
  1. 1.Adolf-Butenandt-Institute, Biochemistry, Ludwig-Maximilians-UniversityMunichGermany
  2. 2.Department of Pathology and Laboratory MedicineUniversity of British ColumbiaVancouverCanada
  3. 3.Adolf-Butenandt-Institute, Protein Analysis UnitLudwig-Maximilians-UniversityMunichGermany
  4. 4.Center for Neuropathology and Prion ResearchLudwig-Maximilians-UniversityMunichGermany
  5. 5.DZNE, German Center for Neurodegenerative DiseasesMunichGermany
  6. 6.Neurodegenerative Brain Diseases Group, Department of Molecular GeneticsVIBAntwerpBelgium
  7. 7.Laboratory of Neurogenetics, Institute Born-BungeUniversity of AntwerpAntwerpBelgium
  8. 8.Munich Cluster for Systems Neurology (SyNergy)MunichGermany
  9. 9.DZNE, German Center for Neurodegenerative DiseasesTübingenGermany
  10. 10.Department of NeuropathologyUniversity of TübingenTübingenGermany

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