Acta Neuropathologica

, Volume 130, Issue 6, pp 845–861 | Cite as

Quantitative analysis and clinico-pathological correlations of different dipeptide repeat protein pathologies in C9ORF72 mutation carriers

  • Ian R. A. Mackenzie
  • Petra Frick
  • Friedrich A. Grässer
  • Tania F. Gendron
  • Leonard Petrucelli
  • Neil R. Cashman
  • Dieter Edbauer
  • Elisabeth Kremmer
  • Johannes Prudlo
  • Dirk Troost
  • Manuela NeumannEmail author
Original Paper


Hexanucleotide repeat expansion in C9ORF72 is the most common genetic cause of frontotemporal dementia and motor neuron disease. One consequence of the mutation is the formation of different potentially toxic polypeptides composed of dipeptide repeats (DPR) (poly-GA, -GP, -GR, -PA, -PR) generated by repeat-associated non-ATG (RAN) translation. While previous studies focusing on poly-GA pathology have failed to detect any clinico-pathological correlations in C9ORF72 mutation cases, recent data from animal and cell culture models suggested that it may be only specific DPR species that are toxic and only when accumulated in certain intracellular compartments. Therefore, we performed a systematic clinico-pathological correlative analysis with counting of actual numbers of distinct types of inclusion (neuronal cytoplasmic and intranuclear inclusions, dystrophic neurites) for each DPR protein in relevant brain regions (premotor cortex, lower motor neurons) in a cohort of 35 C9ORF72 mutation cases covering the clinical spectrum from those with pure MND, mixed FTD/MND and pure FTD. While each DPR protein pathology had a similar pattern of anatomical distribution, the total amount of inclusions for each DPR protein varied remarkably (poly-GA > GP > GR > PR/PA), indicating that RAN translation seems to be more effective from sense than from antisense transcripts. Importantly, with the exception of moderate associations for the amount of poly-GA-positive dystrophic neurites with degeneration in the frontal cortex and total burden of poly-GA pathology with disease onset, no relationship was identified for any other DPR protein pathology with degeneration or phenotype. Biochemical analysis revealed a close correlation between insoluble DPR protein species and numbers of visible inclusions, while we did not find any evidence for the presence of soluble DPR protein species. Thus, overall our findings strongly argue against a role of DPR protein aggregation as major and exclusive pathomechanism in C9ORF72 pathogenesis. However, this does not exclude that DPR protein formation might be essential in C9ORF72 pathogenesis in interplay with other consequences associated with the C9ORF72 repeat expansion.


Antisense Transcript Motor Neuron Disease Lower Motor Neuron Dystrophic Neurites Neuronal Cytoplasmic Inclusion 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We would like to thank Margaret Luk, Katrin Trautmann and Manuel Gödan for their excellent technical assistance. This work was supported by the German Helmholtz Association (VH-VI-510 and W2/W3-036, MN), the Canadian Institutes of Health Research (74580, IRM), the Pacific Alzheimer’s Research Foundation (C06-01, IRM), and the European Unions’s Seventh Framework Program (FP7/2014-2019 Grant 617198, DE).

Supplementary material

401_2015_1476_MOESM1_ESM.pdf (1.3 mb)
Supplementary material 1 (PDF 1322 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Ian R. A. Mackenzie
    • 1
  • Petra Frick
    • 2
  • Friedrich A. Grässer
    • 3
  • Tania F. Gendron
    • 4
  • Leonard Petrucelli
    • 4
  • Neil R. Cashman
    • 5
  • Dieter Edbauer
    • 6
    • 7
    • 8
  • Elisabeth Kremmer
    • 7
    • 9
  • Johannes Prudlo
    • 10
    • 11
  • Dirk Troost
    • 12
  • Manuela Neumann
    • 2
    • 13
    Email author
  1. 1.Department of PathologyUniversity of British Columbia and Vancouver General HospitalVancouverCanada
  2. 2.German Center for Neurodegenerative Diseases (DZNE)TübingenGermany
  3. 3.Institute of VirologySaarland University Medical SchoolHomburgGermany
  4. 4.Department of NeuroscienceMayo Clinic FloridaJacksonvilleUSA
  5. 5.Department of Medicine (Neurology), Brain Research CentreUniversity of British ColumbiaVancouverCanada
  6. 6.German Center for Neurodegenerative Diseases (DZNE)MunichGermany
  7. 7.Munich Cluster of Systems Neurology (SyNergy)MunichGermany
  8. 8.Institute for Metabolic BiochemistryLudwig-Maximilians University MunichMunichGermany
  9. 9.Institute of Molecular ImmunologyHelmholtz Zentrum MünchenMunichGermany
  10. 10.German Center for Neurodegenerative Diseases (DZNE)RostockGermany
  11. 11.Department of NeurologyUniversity of RostockRostockGermany
  12. 12.Department of Neuropathology, Academic Medical CentreUniversity of AmsterdamAmsterdamThe Netherlands
  13. 13.Department of NeuropathologyUniversity of TübingenTübingenGermany

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