Original Paper

Acta Neuropathologica

, Volume 125, Issue 2, pp 289-302

First online:

Tau pathology in frontotemporal lobar degeneration with C9ORF72 hexanucleotide repeat expansion

  • Kevin F. BieniekAffiliated withDepartment of Neuroscience, Mayo Clinic
  • , Melissa E. MurrayAffiliated withDepartment of Neuroscience, Mayo Clinic
  • , Nicola J. RutherfordAffiliated withDepartment of Neuroscience, Mayo Clinic
  • , Monica Castanedes-CaseyAffiliated withDepartment of Neuroscience, Mayo Clinic
  • , Mariely DeJesus-HernandezAffiliated withDepartment of Neuroscience, Mayo Clinic
  • , Amanda M. LiesingerAffiliated withDepartment of Neuroscience, Mayo Clinic
  • , Matthew C. BakerAffiliated withDepartment of Neuroscience, Mayo Clinic
  • , Kevin B. BoylanAffiliated withDepartment of Neurology, Mayo Clinic
  • , Rosa RademakersAffiliated withDepartment of Neuroscience, Mayo Clinic

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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