Acta Neuropathologica

, Volume 126, Issue 6, pp 859–879 | Cite as

Dipeptide repeat protein pathology in C9ORF72 mutation cases: clinico-pathological correlations

  • Ian R. Mackenzie
  • Thomas Arzberger
  • Elisabeth Kremmer
  • Dirk Troost
  • Stefan Lorenzl
  • Kohji Mori
  • Shih-Ming Weng
  • Christian Haass
  • Hans A. Kretzschmar
  • Dieter Edbauer
  • Manuela Neumann
Original Paper


Hexanucleotide repeat expansion in C9ORF72 is the most common genetic cause of frontotemporal dementia and motor neuron disease. Recently, unconventional non-ATG translation of the expanded hexanucleotide repeat, resulting in the production and aggregation of dipeptide repeat (DPR) proteins (poly-GA, -GR and GP), was identified as a potential pathomechanism of C9ORF72 mutations. Besides accumulation of DPR proteins, the second neuropathological hallmark lesion in C9ORF72 mutation cases is the accumulation of TDP-43. In this study, we characterized novel monoclonal antibodies against poly-GA and performed a detailed analysis of the neuroanatomical distribution of DPR and TDP-43 pathology in a cohort of 35 cases with the C9ORF72 mutation that included a broad spectrum of clinical phenotypes. We found the pattern of DPR pathology to be highly consistent among cases regardless of the phenotype with high DPR load in the cerebellum, all neocortical regions (frontal, motor cortex and occipital) and hippocampus, moderate pathology in subcortical areas and minimal pathology in lower motor neurons. No correlation between DPR pathology and the degree of neurodegeneration was observed, while a good association between TDP-43 pathology with clinical phenotype and degeneration in key anatomical regions was present. Our data confirm that the presence of DPR pathology is intimately related to C9ORF72 mutations. The observed dissociation between DPR inclusion body load and neurodegeneration might suggest inclusion body formation as a potentially protective response to cope with soluble toxic DPR species. Moreover, our data imply that alterations due to the C9ORF72 mutation resulting in TDP-43 accumulation and dysmetabolism as secondary downstream effects likely play a central role in the neurodegenerative process in C9ORF72 pathogenesis.


C9orf72 Motor neuron disease Frontotemporal dementia TDP-43 Non-ATG translation 



We would like to thank Katrin Trautmann, Margaret Luk, Brigitte Kraft and Michael Schmidt for their excellent technical assistance. This work was supported by grants from the German Helmholtz Association (VH-VI-510, MN), the German Federal Ministry of Education and Research (01GI0704, MN), the Alexander von Humboldt Foundation (KM), the Canadian Institutes of Health Research (74580, IRM), the Pacific Alzheimer’s Research Foundation (C06-01, IRM), the Centres of Excellence in Neurodegeneration Research (CoEN, DE and CH) and the Helmholtz Young Investigator (DE) and W2/W3 program (MN).

Supplementary material

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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Ian R. Mackenzie
    • 1
  • Thomas Arzberger
    • 2
    • 3
  • Elisabeth Kremmer
    • 2
    • 4
  • Dirk Troost
    • 5
  • Stefan Lorenzl
    • 6
  • Kohji Mori
    • 7
  • Shih-Ming Weng
    • 2
  • Christian Haass
    • 2
    • 7
    • 8
  • Hans A. Kretzschmar
    • 3
  • Dieter Edbauer
    • 2
    • 7
    • 8
  • Manuela Neumann
    • 9
    • 10
  1. 1.Department of Pathology, Vancouver General HospitalUniversity of British ColumbiaVancouverCanada
  2. 2.DZNE Munich, German Center for Neurodegenerative DiseasesMunichGermany
  3. 3.Center for Neuropathology and Prion ResearchLudwig-Maximilians-UniversityMunichGermany
  4. 4.Institute of Molecular ImmunologyHelmholtz Zentrum MünchenMunichGermany
  5. 5.Department of Neuropathology, Academic Medical CentreUniversity of AmsterdamAmsterdamThe Netherlands
  6. 6.Department of Palliative Care and Department of NeurologyLudwig-Maximilians-UniversityMunichGermany
  7. 7.Adolf Butenandt Institute, BiochemistryLudwig-Maximilians UniversityMunichGermany
  8. 8.Munich Cluster of Systems Neurology (SyNergy)MunichGermany
  9. 9.Department of NeuropathologyUniversity of TübingenTübingenGermany
  10. 10.DZNE, German Center for Neurodegenerative DiseasesTübingenGermany

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