Acta Neuropathologica

, Volume 125, Issue 2, pp 289–302 | Cite as

Tau pathology in frontotemporal lobar degeneration with C9ORF72 hexanucleotide repeat expansion

  • Kevin F. Bieniek
  • Melissa E. Murray
  • Nicola J. Rutherford
  • Monica Castanedes-Casey
  • Mariely DeJesus-Hernandez
  • Amanda M. Liesinger
  • Matthew C. Baker
  • Kevin B. Boylan
  • Rosa Rademakers
  • Dennis W. DicksonEmail author
Original Paper


An expanded GGGGCC hexanucleotide repeat in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal lobar degeneration associated with TDP-43 pathology (FTLD-TDP). In addition to TDP-43-positive neuronal and glial inclusions, C9ORF72-linked FTLD-TDP has characteristic TDP-43-negative neuronal cytoplasmic and intranuclear inclusions as well as dystrophic neurites in the hippocampus and cerebellum. These lesions are immunopositive for ubiquitin and ubiquitin-binding proteins, such as sequestosome-1/p62 and ubiquilin-2. Studies examining the frequency of the C9ORF72 mutation in clinically probable Alzheimer’s disease (AD) have found a small proportion of AD cases with the mutation. This prompted us to systematically explore the frequency of Alzheimer-type pathology in a series of 17 FTLD-TDP cases with mutations in C9ORF72 (FTLD-C9ORF72). We identified four cases with sufficient Alzheimer-type pathology to meet criteria for intermediate-to-high-likelihood AD. We compared AD pathology in the 17 FTLD-C9ORF72 to 13 cases of FTLD-TDP linked to mutations in the gene for progranulin (FTLD-GRN) and 36 cases of sporadic FTLD (sFTLD). FTLD-C9ORF72 cases had higher Braak neurofibrillary tangle stage than FTLD-GRN. Increased tau pathology in FTLD-C9ORF72 was assessed with thioflavin-S fluorescent microscopy-based neurofibrillary tangle counts and with image analysis of tau burden in temporal cortex and hippocampus. FTLD-C9ORF72 had significantly more neurofibrillary tangles and higher tau burden compared with FTLD-GRN. The differences were most marked in limbic regions. On the other hand, sFTLD and FTLD-C9ORF72 had a similar burden of tau pathology. These results suggest FTLD-C9ORF72 has increased propensity for tau pathology compared to FTLD-GRN, but not sFTLD. The accumulation of tau as well as lesions immunoreactive for ubiquitin and ubiquitin-binding proteins (p62 and ubiquilin-2) suggests that mutations in C9ORF72 may involve disrupted protein degradation that favors accumulation of multiple different proteins.


Frontotemporal lobar degeneration C9ORF72 Ubiquitin P62 Ubiquilin-2 Tau 



We are grateful to all patients, family members, and caregivers who agreed to brain donation, without which these studies would have been impossible. We also acknowledge expert technical assistance of Linda Rousseau and Virginia Phillips for histology and John Gonzalez, Beth Marten, Pamela Desaro and Amelia Johnston for brain banking. This research was funded by Mayo Foundation (Jacoby Professorship of Alzheimer Research, Research Committee CR Program; ALS Center donor funds); National Institutes of Health (P50-AG16574, P50-NS72187, P01-AG03949, R01-AG37491, R01-NS65782 and R01-AG26251), CurePSP, The Society for Progressive Supranuclear Palsy; and the State of Florida Alzheimer Disease Initiative.

Supplementary material

401_2012_1048_MOESM1_ESM.tif (10.1 mb)
Supplementary Fig. 1 Quantitative analysis of PHF-1 immunostaining in the CA1 of a FTLD-C9ORF72 case (Case 10). The CA1 sector of hippocampus is selected as a region of interest. A color deconvolution algorithm, tuned to PHF-1 staining with DAB chromogen, was applied to the image to detect the number of pixels that are strongly immunostained (red) compared to the unstained background (blue). The percentage of these strongly stained pixels is outputted as a quantitative variable and statistically analyzed. (bar = 200 µm) (TIFF 10365 kb)
401_2012_1048_MOESM2_ESM.tif (9.1 mb)
Supplementary Fig. 2 Double-labeling of ubiquitin-binding proteins p62 and Ubqln2 in the cerebellum of a FTLD-C9ORF72 case (Case 16). Staining was processed on the Dako Autostainer using the Dako EnVision™ G|2 Doublestain system (DAKO, Carpinteria, CA, USA). P62 lesions are labeled with the diaminobenzidine chromogen (brown) and the Ubqln2 lesions labeled with the Vector Blue chromogen (blue)(Vector Laboratories, Burlingame, CA, USA). P62-immunopositive NCIs are seen in both Purkinje and granule cells whereas Ubqln2-immunopositive NCIs are seen in the granule cell layer. There is variable overlap in immunoreactivity between these two proteins. (bar = 20 µm, inset approx. 50 µm) (TIFF 9300 kb)
401_2012_1048_MOESM3_ESM.docx (36 kb)
Supplementary material 3 (DOCX 36 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Kevin F. Bieniek
    • 1
  • Melissa E. Murray
    • 1
  • Nicola J. Rutherford
    • 1
  • Monica Castanedes-Casey
    • 1
  • Mariely DeJesus-Hernandez
    • 1
  • Amanda M. Liesinger
    • 1
  • Matthew C. Baker
    • 1
  • Kevin B. Boylan
    • 2
  • Rosa Rademakers
    • 1
  • Dennis W. Dickson
    • 1
    Email author
  1. 1.Department of NeuroscienceMayo ClinicJacksonvilleUSA
  2. 2.Department of NeurologyMayo ClinicJacksonvilleUSA

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