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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

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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.

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References

  1. Alafuzoff I, Arzberger T, Al-Sarraj S et al (2008) Staging of neurofibrillary pathology in Alzheimer’s disease: a study of the BrainNet Europe Consortium. Brain Pathol 18:484–496

    PubMed  Google Scholar 

  2. Arai T, Hasegawa M, Akiyama H et al (2006) TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun 351:602–611

    Article  PubMed  CAS  Google Scholar 

  3. Becher MW, Kotzuk JA, Sharp AH et al (1998) Intranuclear neuronal inclusions in Huntington’s disease and dentatorubral and pallidoluysian atrophy: correlation between the density of inclusions and IT15 CAG triplet repeat length. Neurobiol Dis 4:387–397

    Article  PubMed  CAS  Google Scholar 

  4. Beck J, Rohrer JD, Campbell T et al (2008) A distinct clinical, neuropsychological and radiological phenotype is associated with progranulin gene mutations in a large UK series. Brain 131:706–720

    Article  PubMed  Google Scholar 

  5. Boxer AL, Mackenzie IR, Boeve BF et al (2010) Clinical, neuroimaging and neuropathological features of a new chromosome 9p-linked FTD-ALS family. J Neurol Neurosurg Psychiatry 82:196–203

    Article  PubMed  Google Scholar 

  6. Cairns NJ, Bigio EH, Mackenzie IR et al (2007) Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the consortium for frontotemporal lobar degeneration. Acta Neuropathol 114:5–22

    Article  PubMed  Google Scholar 

  7. Cairns NJ, Neumann M, Bigio EH et al (2007) TDP-43 in familial and sporadic frontotemporal lobar degeneration with ubiquitin inclusions. Am J Pathol 171:227–240

    Article  PubMed  CAS  Google Scholar 

  8. Dejesus-Hernandez M, Mackenzie IR, Boeve BF et al (2011) Expanded GGGGCC Hexanucleotide Repeat in Noncoding Region of C9ORF72 Causes Chromosome 9p-Linked FTD and ALS. Neuron 72:245–256

    Article  PubMed  CAS  Google Scholar 

  9. Deng HX, Chen W, Hong ST et al (2011) Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature 477:211–215

    Article  PubMed  CAS  Google Scholar 

  10. Geser F, Brandmeir NJ, Kwong LK et al (2008) Evidence of multisystem disorder in whole-brain map of pathological TDP-43 in amyotrophic lateral sclerosis. Arch Neurol 65:636–641

    Article  PubMed  Google Scholar 

  11. Jackson M, Lennox G, Lowe J (1996) Motor neurone disease-inclusion dementia. Neurodegeneration 5:339–350

    Article  PubMed  CAS  Google Scholar 

  12. Johnson JO, Mandrioli J, Benatar M et al (2010) Exome sequencing reveals VCP mutations as a cause of familial ALS. Neuron 68:857–864

    Article  PubMed  CAS  Google Scholar 

  13. King A, Al-Sarraj S, Shaw C (2009) Frontotemporal lobar degeneration with ubiquitinated tau-negative inclusions and additional alpha-synuclein pathology but also unusual cerebellar ubiquitinated p62-positive, TDP-43-negative inclusions. Neuropathology 29:466–471

    Article  PubMed  Google Scholar 

  14. King A, Maekawa S, Bodi I et al (2011) Ubiquitinated, p62 immunopositive cerebellar cortical neuronal inclusions are evident across the spectrum of TDP-43 proteinopathies but are only rarely additionally immunopositive for phosphorylation-dependent TDP-43. Neuropathology 31:239–249

    Article  PubMed  Google Scholar 

  15. Laaksovirta H, Peuralinna T, Schymick JC et al (2010) Chromosome 9p21 in amyotrophic lateral sclerosis in Finland: a genome-wide association study. Lancet Neurol 9:978–985

    Article  PubMed  CAS  Google Scholar 

  16. Leigh PN, Anderton BH, Dodson A et al (1988) Ubiquitin deposits in anterior horn cells in motor neurone disease. Neurosci Lett 93:197–203

    Article  PubMed  CAS  Google Scholar 

  17. Lowe J, Lennox G, Jefferson D et al (1988) A filamentous inclusion body within anterior horn neurones in motor neurone disease defined by immunocytochemical localisation of ubiquitin. Neurosci Lett 94:203–210

    Article  PubMed  CAS  Google Scholar 

  18. Mackenzie IR (2007) The neuropathology and clinical phenotype of FTD with progranulin mutations. Acta Neuropathol 114:49–54

    Article  PubMed  Google Scholar 

  19. Mackenzie IR, Baker M, Pickering-Brown S et al (2006) The neuropathology of frontotemporal lobar degeneration caused by mutations in the progranulin gene. Brain 129:3081–3090

    Article  PubMed  Google Scholar 

  20. Mackenzie IR, Neumann M, Bigio EH et al (2010) Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update. Acta Neuropathol 119:1–4

    Article  PubMed  Google Scholar 

  21. Maekawa S, Leigh PN, King A et al (2009) TDP-43 is consistently co-localized with ubiquitinated inclusions in sporadic and Guam amyotrophic lateral sclerosis but not in familial amyotrophic lateral sclerosis with and without SOD1 mutations. Neuropathology 29:672–683

    Article  PubMed  Google Scholar 

  22. Maruyama H, Morino H, Ito H et al (2010) Mutations of optineurin in amyotrophic lateral sclerosis. Nature 465:223–226

    Article  PubMed  CAS  Google Scholar 

  23. Morita M, Al-Chalabi A, Andersen PM et al (2006) A locus on chromosome 9p confers susceptibility to ALS and frontotemporal dementia. Neurology 66:839–844

    Article  PubMed  CAS  Google Scholar 

  24. Neumann M, Mackenzie IR, Cairns NJ et al (2007) TDP-43 in the ubiquitin pathology of frontotemporal dementia with VCP gene mutations. J Neuropathol Exp Neurol 66:152–157

    Article  PubMed  Google Scholar 

  25. Neumann M, Sampathu DM, Kwong LK et al (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130–133

    Article  PubMed  CAS  Google Scholar 

  26. Pikkarainen M, Hartikainen P, Alafuzoff I (2008) Neuropathologic features of frontotemporal lobar degeneration with ubiquitin-positive inclusions visualized with ubiquitin-binding protein p62 immunohistochemistry. J Neuropathol Exp Neurol 67:280–298

    Article  PubMed  Google Scholar 

  27. Renton AE, Majounie E, Waite A et al (2011) A Hexanucleotide Repeat Expansion in C9ORF72 Is the Cause of Chromosome 9p21-Linked ALS-FTD. Neuron 72:257–268

    Article  PubMed  CAS  Google Scholar 

  28. Sampathu DM, Neumann M, Kwong LK et al (2006) Pathological heterogeneity of frontotemporal lobar degeneration with ubiquitin-positive inclusions delineated by ubiquitin immunohistochemistry and novel monoclonal antibodies. Am J Pathol 169:1343–1352

    Article  PubMed  CAS  Google Scholar 

  29. Shatunov A, Mok K, Newhouse S et al (2010) Chromosome 9p21 in sporadic amyotrophic lateral sclerosis in the UK and seven other countries: a genome-wide association study. Lancet Neurol 9:986–994

    Article  PubMed  CAS  Google Scholar 

  30. Sreedharan J, Blair IP, Tripathi VB et al (2008) TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319:1668–1672

    Article  PubMed  CAS  Google Scholar 

  31. Todd PK, Paulson HL (2010) RNA-mediated neurodegeneration in repeat expansion disorders. Ann Neurol 67:291–300

    Article  PubMed  CAS  Google Scholar 

  32. Van Deerlin VM, Sleiman PM, Martinez-Lage M et al (2010) Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions. Nat Genet 42:234–239

    Article  PubMed  Google Scholar 

  33. Vance C, Al-Chalabi A, Ruddy D et al (2006) Familial amyotrophic lateral sclerosis with frontotemporal dementia is linked to a locus on chromosome 9p13.2-21.3. Brain 129:868–876

    Article  PubMed  Google Scholar 

  34. Wooten MW, Hu X, Babu JR et al (2006) Signaling, polyubiquitination, trafficking, and inclusions: sequestosome 1/p62’s role in neurodegenerative disease. J Biomed Biotechnol 2006:62079

    Article  PubMed  Google Scholar 

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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.

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The authors declare they have no conflict of interest.

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Correspondence to Andrew King.

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The authors S. Al-Sarraj and A. King have made an equal contribution.

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Al-Sarraj, S., King, A., Troakes, C. et al. 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. Acta Neuropathol 122, 691–702 (2011). https://doi.org/10.1007/s00401-011-0911-2

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  • DOI: https://doi.org/10.1007/s00401-011-0911-2

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