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Acta Neuropathologica

, Volume 122, Issue 6, pp 691–702 | Cite as

p62 positive, TDP-43 negative, neuronal cytoplasmic and intranuclear inclusions in the cerebellum and hippocampus define the pathology of C9orf72-linked FTLD and MND/ALS

  • Safa Al-Sarraj
  • Andrew KingEmail author
  • Claire Troakes
  • Bradley Smith
  • Satomi Maekawa
  • Istvan Bodi
  • Boris Rogelj
  • Ammar Al-Chalabi
  • Tibor Hortobágyi
  • Christopher E. Shaw
Original Paper

Abstract

Neuronal cytoplasmic inclusions (NCIs) containing phosphorylated TDP-43 (p-TDP-43) are the pathological hallmarks of motor neuron disease/amyotrophic lateral sclerosis (MND/ALS) and FTLD-TDP. The vast majority of NCIs in the brain and spinal cord also label for ubiquitin and p62, however, we have previously reported a subset of TDP-43 proteinopathy patients who have unusual and abundant p62 positive, TDP-43 negative inclusions in the cerebellum and hippocampus. Here we sought to determine whether these cases carry the hexanucleotide repeat expansion in C9orf72. Repeat primer PCR was performed in 36 MND/ALS, FTLD-MND/ALS and FTLD-TDP cases and four controls. Fourteen individuals with the repeat expansion were detected. In all the 14 expansion mutation cases there were abundant globular and star-shaped p62 positive NCIs in the pyramidal cell layer of the hippocampus, the vast majority of which were p-TDP-43 negative. p62 positive NCIs were also abundant in the cerebellar granular and molecular layers in all cases and in Purkinje cells in 12/14 cases but they were only positive for p-TDP-43 in the granular layer of one case. Abundant p62 positive, p-TDP-43 negative neuronal intranuclear inclusions (NIIs) were seen in 12/14 cases in the pyramidal cell layer of the hippocampus and in 6/14 cases in the cerebellar granular layer. This unusual combination of inclusions appears pathognomonic for C9orf72 repeat expansion positive MND/ALS and FTLD-TDP which we believe form a pathologically distinct subset of TDP-43 proteinopathies. Our results suggest that proteins other than TDP-43 are binding p62 and aggregating in response to the mutation which may play a mechanistic role in neurodegeneration.

Keywords

MND/ALS FTLD C9orf72 p62 TDP43 

Notes

Acknowledgments

The authors thank the donors and their families whose donation of brain and spinal cord tissue to the Medical Research Council London Neurodegenerative Diseases Brain Bank allowed this research to take place. The authors thank Professor Martin Rossor for referral of GRN mutation cases. They also thank the staff of the Clinical Neuropathology Department, King’s College Hospital, especially Mary Davitt and Joanne Hickey. Funding to support this work came from the Motor Neuron Disease Association, American Amyotrophic Lateral Sclerosis Association, Heaton-Ellis Trust, Medical Research Council (UK), Wellcome Trust and Psychiatry Research Trust.

Conflict of interest

The authors declare they have no conflict of interest.

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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Safa Al-Sarraj
    • 1
    • 2
    • 3
  • Andrew King
    • 1
    • 2
    Email author
  • Claire Troakes
    • 2
    • 3
  • Bradley Smith
    • 3
  • Satomi Maekawa
    • 1
    • 2
    • 3
  • Istvan Bodi
    • 1
    • 2
  • Boris Rogelj
    • 3
  • Ammar Al-Chalabi
    • 2
    • 3
  • Tibor Hortobágyi
    • 2
    • 3
  • Christopher E. Shaw
    • 2
    • 3
  1. 1.Department of Clinical NeuropathologyAcademic Neuroscience Building, Kings College HospitalLondonUK
  2. 2.MRC London Neurodegenerative Diseases Brain BankInstitute of Psychiatry, Kings CollegeLondonUK
  3. 3.Department of Clinical NeuroscienceMRC Centre for Neurodegeneration Research, Institute of Psychiatry, Kings CollegeLondonUK

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