Acta Neuropathologica

, Volume 127, Issue 3, pp 347–357 | Cite as

The neuropathology associated with repeat expansions in the C9ORF72 gene

  • Ian R. A. Mackenzie
  • Petra Frick
  • Manuela Neumann
Review

Abstract

An abnormal expansion of a GGGGCC hexanucleotide repeat in a non-coding region of the chromosome 9 open reading frame 72 gene (C9ORF72) is the most common genetic abnormality in familial and sporadic FTLD and ALS and the cause in most families where both, FTLD and ALS, are inherited. Pathologically, C9ORF72 expansion cases show a combination of FTLD-TDP and classical ALS with abnormal accumulation of TDP-43 into neuronal and oligodendroglial inclusions consistently seen in the frontal and temporal cortex, hippocampus and pyramidal motor system. In addition, a highly specific feature in C9ORF72 expansion cases is the presence of ubiquitin and p62 positive, but TDP-43 negative neuronal cytoplasmic and intranuclear inclusions. These TDP-43 negative inclusions contain dipeptide-repeat (DPR) proteins generated by unconventional repeat-associated translation of C9ORF72 transcripts with the expanded repeats and are most abundant in the cerebellum, hippocampus and all neocortex regions. Another consistent pathological feature associated with the production of C9ORF72 transcripts with expanded repeats is the formation of nuclear RNA foci that are frequently observed in the frontal cortex, hippocampus and cerebellum. Here, we summarize the complexity and heterogeneity of the neuropathology associated with the C9ORF72 expansion. We discuss implications of the data to the current classification of FTLD and critically review current insights from clinico-pathological correlative studies regarding the fundamental questions as to what processes are required and sufficient to trigger neurodegeneration in C9ORF72 disease pathogenesis.

References

  1. 1.
    Al-Sarraj S, King A, Troakes C, Smith B, Maekawa S, Bodi I et al (2011) 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. doi:10.1007/s00401-011-0911-2 PubMedCrossRefGoogle Scholar
  2. 2.
    Almeida S, Gascon E, Tran H, Chou HJ, Gendron TF, Degroot S et al (2013) Modeling key pathological features of frontotemporal dementia with C9ORF72 repeat expansion in iPSC-derived human neurons. Acta Neuropathol 126:385–399. doi:10.1007/s00401-013-1149-y PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Arai T, Mackenzie IR, Hasegawa M, Nonoka T, Niizato K, Tsuchiya K et al (2009) Phosphorylated TDP-43 in Alzheimer’s disease and dementia with Lewy bodies. Acta Neuropathol 117:125–136. doi:10.1007/s00401-008-0480-1 PubMedCrossRefGoogle Scholar
  4. 4.
    Ash PE, Bieniek KF, Gendron TF, Caulfield T, Lin WL, Dejesus-Hernandez M et al (2013) Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. Neuron 77:639–646. doi:10.1016/j.neuron.2013.02.004 PubMedCrossRefGoogle Scholar
  5. 5.
    Belzil VV, Bauer PO, Prudencio M, Gendron TF, Stetler CT, Yan IK et al (2013) Reduced C9orf72 gene expression in c9FTD/ALS is caused by histone trimethylation, an epigenetic event detectable in blood. Acta Neuropathol 126:895–905. doi:10.1007/s00401-013-1199-1 PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Belzil VV, Gendron TF, Petrucelli L (2013) RNA-mediated toxicity in neurodegenerative disease. Mol Cell Neurosci 56:406–419. doi:10.1016/j.mcn.2012.12.006 PubMedCrossRefGoogle Scholar
  7. 7.
    Bieniek KF, Murray ME, Rutherford NJ, Castanedes-Casey M, DeJesus-Hernandez M, Liesinger AM et al (2013) Tau pathology in frontotemporal lobar degeneration with C9ORF72 hexanucleotide repeat expansion. Acta Neuropathol 125:289–302. doi:10.1007/s00401-012-1048-7 PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Boeve BF, Boylan KB, Graff-Radford NR, DeJesus-Hernandez M, Knopman DS, Pedraza O et al (2012) Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72. Brain 135:765–783. doi:10.1093/brain/aws004 PubMedCrossRefGoogle Scholar
  9. 9.
    Boxer AL, Mackenzie IR, Boeve BF, Baker M, Seeley WW, Crook R et al (2011) Clinical, neuroimaging and neuropathological features of a new chromosome 9p-linked FTD-ALS family. J Neurol Neurosurg Psychiatry 82:196–203. doi:10.1136/jnnp.2009.204081 PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Brettschneider J, Van Deerlin VM, Robinson JL, Kwong L, Lee EB, Ali YO et al (2012) Pattern of ubiquilin pathology in ALS and FTLD indicates presence of C9ORF72 hexanucleotide expansion. Acta Neuropathol 123:825–839. doi:10.1007/s00401-012-0970-z PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Buratti E, Baralle FE (2010) The multiple roles of TDP-43 in pre-mRNA processing and gene expression regulation. RNA Biol 7:420–429 (pii: 12205)PubMedCrossRefGoogle Scholar
  12. 12.
    Burrell JR, Kiernan MC, Vucic S, Hodges JR (2011) Motor neuron dysfunction in frontotemporal dementia. Brain 134:2582–2594. doi:10.1093/brain/awr195 PubMedCrossRefGoogle Scholar
  13. 13.
    Cairns NJ, Neumann M, Bigio EH, Holm IE, Troost D, Hatanpaa KJ et al (2007) TDP-43 in familial and sporadic frontotemporal lobar degeneration with ubiquitin inclusions. Am J Pathol 171:227–240PubMedCrossRefGoogle Scholar
  14. 14.
    Ciura S, Lattante S, Le Ber I, Latouche M, Tostivint H, Brice A et al (2013) Loss of function of C9orf72 causes motor deficits in a zebrafish model of Amyotrophic Lateral Sclerosis. Ann Neurol. doi:10.1002/ana.23946 PubMedGoogle Scholar
  15. 15.
    Cleary JD, Ranum LP (2013) Repeat-associated non-ATG (RAN) translation in neurological disease. Hum Mol Genet 22:R45–R51. doi:10.1093/hmg/ddt371 PubMedCrossRefGoogle Scholar
  16. 16.
    Cooper-Knock J, Hewitt C, Highley JR, Brockington A, Milano A, Man S et al (2012) Clinico-pathological features in amyotrophic lateral sclerosis with expansions in C9ORF72. Brain 135:751–764. doi:10.1093/brain/awr365 PubMedCrossRefGoogle Scholar
  17. 17.
    Da Cruz S, Cleveland DW (2011) Understanding the role of TDP-43 and FUS/TLS in ALS and beyond. Curr Opin Neurobiol 21:904–919. doi:10.1016/j.conb.2011.05.029 PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Davidson Y, Kelley T, Mackenzie IR, Pickering-Brown S, Du Plessis D, Neary D et al (2007) Ubiquitinated pathological lesions in frontotemporal lobar degeneration contain the TAR DNA-binding protein, TDP-43. Acta Neuropathol 113:521–533. doi:10.1007/s00401-006-0189-y PubMedCrossRefGoogle Scholar
  19. 19.
    DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ et al (2011) Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72:245–256. doi:10.1016/j.neuron.2011.09.011 PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Dickson DW, Baker M, Rademakers R (2010) Common variant in GRN is a genetic risk factor for hippocampal sclerosis in the elderly. Neurodegener Dis 7:170–174. doi:10.1159/000289231 PubMedCrossRefGoogle Scholar
  21. 21.
    Donnelly CJ, Zhang PW, Pham JT, Heusler AR, Mistry NA, Vidensky S et al (2013) RNA Toxicity from the ALS/FTD C9ORF72 Expansion Is Mitigated by Antisense Intervention. Neuron 80:415–428. doi:10.1016/j.neuron.2013.10.015 PubMedCrossRefGoogle Scholar
  22. 22.
    Gendron TF, Bieniek KF, Zhang YJ, Jansen-West K, Ash PE, Caulfield T et al (2013) Antisense transcripts of the expanded C9ORF72 hexanucleotide repeat form nuclear RNA foci and undergo repeat-associated non-ATG translation in c9FTD/ALS. Acta Neuropathol 126:829–844. doi:10.1007/s00401-013-1192-8 PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Gijselinck I, Engelborghs S, Maes G, Cuijt I, Peeters K, Mattheijssens M et al (2010) Identification of 2 Loci at chromosomes 9 and 14 in a multiplex family with frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Arch Neurol 67:606–616. doi:10.1001/archneurol.2010.82 PubMedCrossRefGoogle Scholar
  24. 24.
    Gijselinck I, Van Langenhove T, van der Zee J, Sleegers K, Philtjens S, Kleinberger G et al (2012) A C9orf72 promoter repeat expansion in a Flanders-Belgian cohort with disorders of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum: a gene identification study. Lancet Neurol 11:54–65. doi:10.1016/S1474-4422(11)70261-7 PubMedCrossRefGoogle Scholar
  25. 25.
    Halliday G, Bigio EH, Cairns NJ, Neumann M, Mackenzie IR, Mann DM (2012) Mechanisms of disease in frontotemporal lobar degeneration: gain of function versus loss of function effects. Acta Neuropathol 124:373–382. doi:10.1007/s00401-012-1030-4 PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Hsiung GY, DeJesus-Hernandez M, Feldman HH, Sengdy P, Bouchard-Kerr P, Dwosh E et al (2012) Clinical and pathological features of familial frontotemporal dementia caused by C9ORF72 mutation on chromosome 9p. Brain 135:709–722. doi:10.1093/brain/awr354 PubMedCrossRefGoogle Scholar
  27. 27.
    Josephs KA, Whitwell JL, Murray ME, Parisi JE, Graff-Radford NR, Knopman DS et al (2013) Corticospinal tract degeneration associated with TDP-43 type C pathology and semantic dementia. Brain 136:455–470. doi:10.1093/brain/aws324 PubMedCrossRefGoogle Scholar
  28. 28.
    Lagier-Tourenne C, Baughn M, Rigo F, Sun S, Liu P, Li HR et al (2013) Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration. Proc Natl Acad Sci USA 110:E4530–E4539. doi:10.1073/pnas.1318835110 PubMedCrossRefGoogle Scholar
  29. 29.
    Lee EB, Lee VM, Trojanowski JQ (2012) Gains or losses: molecular mechanisms of TDP43-mediated neurodegeneration. Nat Rev Neurosci 13:38–50. doi:10.1038/nrn3121nrn3121 Google Scholar
  30. 30.
    Lee YB, Chen HJ, Peres JN, Gomez-Deza J, Attig J, Stalekar M et al (2013) Hexanucleotide Repeats in ALS/FTD Form Length-Dependent RNA Foci, Sequester RNA Binding Proteins, and Are Neurotoxic. Cell reports. doi:10.1016/j.celrep.2013.10.049 Google Scholar
  31. 31.
    Lomen-Hoerth C, Anderson T, Miller B (2002) The overlap of amyotrophic lateral sclerosis and frontotemporal dementia. Neurology 59:1077–1079PubMedCrossRefGoogle Scholar
  32. 32.
    Lomen-Hoerth C, Murphy J, Langmore S, Kramer JH, Olney RK, Miller B (2003) Are amyotrophic lateral sclerosis patients cognitively normal? Neurology 60:1094–1097PubMedCrossRefGoogle Scholar
  33. 33.
    Luty AA, Kwok JB, Thompson EM, Blumbergs P, Brooks WS, Loy CT et al (2008) Pedigree with frontotemporal lobar degeneration—motor neuron disease and Tar DNA binding protein-43 positive neuropathology: genetic linkage to chromosome 9. BMC Neurol 8:32. doi:10.1186/1471-2377-8-32 PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Mackenzie IR, Baborie A, Pickering-Brown S, Plessis DD, Jaros E, Perry RH et al (2006) Heterogeneity of ubiquitin pathology in frontotemporal lobar degeneration: classification and relation to clinical phenotype. Acta Neuropathol 112:539–549PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Mackenzie IR, Baker M, Pickering-Brown S, Hsiung GY, Lindholm C, Dwosh E et al (2006) The neuropathology of frontotemporal lobar degeneration caused by mutations in the progranulin gene. Brain 129:3081–3090. doi:10.1093/brain/awl271 PubMedCrossRefGoogle Scholar
  36. 36.
    Mackenzie IR, Bigio EH, Ince PG, Geser F, Neumann M, Cairns NJ et al (2007) Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations. Ann Neurol 61:427–434. doi:10.1002/ana.21147 PubMedCrossRefGoogle Scholar
  37. 37.
    Mackenzie IR, Neumann M, Bigio EH, Cairns NJ, Alafuzoff I, Kril J et al (2009) Nomenclature for neuropathologic subtypes of frontotemporal lobar degeneration: consensus recommendations. Acta Neuropathol 117:15–18. doi:10.1007/s00401-008-0460-5 PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    Mackenzie IR, Neumann M, Bigio EH, Cairns NJ, Alafuzoff I, Kril J et al (2010) Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update. Acta Neuropathol 119:1–4. doi:10.1007/s00401-009-0612-2 PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Mackenzie IR, Rademakers R, Neumann M (2010) TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia. Lancet Neurol 9:995–1007. doi:10.1016/S1474-4422(10)70195-2 PubMedCrossRefGoogle Scholar
  40. 40.
    Mackenzie IR, Neumann M, Baborie A, Sampathu DM, Du Plessis D, Jaros E et al (2011) A harmonized classification system for FTLD-TDP pathology. Acta Neuropathol 122:111–113. doi:10.1007/s00401-011-0845-8 PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    Mackenzie IR, Arzberger T, Kremmer E, Troost D, Lorenzl S, Mori K et al (2013) Dipeptide repeat protein pathology in C9ORF72 mutation cases: clinico-pathological correlations. Acta Neuropathol 126:859–879. doi:10.1007/s00401-013-1181-y PubMedCrossRefGoogle Scholar
  42. 42.
    Mahoney CJ, Beck J, Rohrer JD, Lashley T, Mok K, Shakespeare T et al (2012) Frontotemporal dementia with the C9ORF72 hexanucleotide repeat expansion: clinical, neuroanatomical and neuropathological features. Brain 135:736–750. doi:10.1093/brain/awr361 PubMedCrossRefGoogle Scholar
  43. 43.
    Mann DM, Rollinson S, Robinson A, Bennion Callister J, Thompson JC, Snowden JS et al (2013) Dipeptide repeat proteins are present in the p62 positive inclusions in patients with frontotemporal lobar degeneration and motor neurone disease associated with expansions in C9ORF72. Acta Neuropathologica Commun 1:68. doi:10.1186/2051-5960-1-68 CrossRefGoogle Scholar
  44. 44.
    Mizielinska S, Lashley T, Norona FE, Clayton EL, Ridler CE, Fratta P et al (2013) C9orf72 frontotemporal lobar degeneration is characterised by frequent neuronal sense and antisense RNA foci. Acta Neuropathol 126:845–857. doi:10.1007/s00401-013-1200-z PubMedCentralPubMedCrossRefGoogle Scholar
  45. 45.
    Mori K, Arzberger T, Grasser FA, Gijselinck I, May S, Rentzsch K et al (2013) Bidirectional transcripts of the expanded C9orf72 hexanucleotide repeat are translated into aggregating dipeptide repeat proteins. Acta Neuropathol 126:881–893. doi:10.1007/s00401-013-1189-3 PubMedCrossRefGoogle Scholar
  46. 46.
    Mori K, Lammich S, Mackenzie IR, Forne I, Zilow S, Kretzschmar H et al (2013) hnRNP A3 binds to GGGGCC repeats and is a constituent of p62-positive/TDP43-negative inclusions in the hippocampus of patients with C9orf72 mutations. Acta Neuropathol 125:413–423. doi:10.1007/s00401-013-1088-7 PubMedCrossRefGoogle Scholar
  47. 47.
    Mori K, Weng SM, Arzberger T, May S, Rentzsch K, Kremmer E et al (2013) The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science 339:1335–1338. doi:10.1126/science.1232927 PubMedCrossRefGoogle Scholar
  48. 48.
    Moseley ML, Zu T, Ikeda Y, Gao W, Mosemiller AK, Daughters RS et al (2006) Bidirectional expression of CUG and CAG expansion transcripts and intranuclear polyglutamine inclusions in spinocerebellar ataxia type 8. Nat Genet 38:758–769. doi:10.1038/ng1827 PubMedCrossRefGoogle Scholar
  49. 49.
    Murray ME, Dejesus-Hernandez M, Rutherford NJ, Baker M, Duara R, Graff-Radford NR et al (2011) Clinical and neuropathologic heterogeneity of c9FTD/ALS associated with hexanucleotide repeat expansion in C9ORF72. Acta Neuropathol 122:673–690. doi:10.1007/s00401-011-0907-y PubMedCentralPubMedCrossRefGoogle Scholar
  50. 50.
    Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT et al (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130–133. doi:10.1126/science.1134108 PubMedCrossRefGoogle Scholar
  51. 51.
    Neumann M, Mackenzie IR, Cairns NJ, Boyer PJ, Markesbery WR, Smith CD et al (2007) TDP-43 in the ubiquitin pathology of frontotemporal dementia with VCP gene mutations. J Neuropathol Exp Neurol 66:152–157. doi:10.1097/nen.0b013e31803020b9 PubMedCrossRefGoogle Scholar
  52. 52.
    Neumann M, Kwong LK, Lee EB, Kremmer E, Flatley A, Xu Y et al (2009) Phosphorylation of S409/410 of TDP-43 is a consistent feature in all sporadic and familial forms of TDP-43 proteinopathies. Acta Neuropathol 117:137–149. doi:10.1007/s00401-008-0477-9 PubMedCentralPubMedCrossRefGoogle Scholar
  53. 53.
    Pearson JP, Williams NM, Majounie E, Waite A, Stott J, Newsway V et al (2011) Familial frontotemporal dementia with amyotrophic lateral sclerosis and a shared haplotype on chromosome 9p. J Neurol 258:647–655. doi:10.1007/s00415-010-5815-x PubMedCrossRefGoogle Scholar
  54. 54.
    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 67:280–298PubMedCrossRefGoogle Scholar
  55. 55.
    Rademakers R, Neumann M, Mackenzie IR (2012) Advances in understanding the molecular basis of frontotemporal dementia. Nat Rev Neurol 8:423–434. doi:10.1038/nrneurol.2012.117 PubMedCentralPubMedGoogle Scholar
  56. 56.
    Renton AE, Majounie E, Waite A, Simon-Sanchez J, Rollinson S, Gibbs JR et al (2011) A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72:257–268. doi:10.1016/j.neuron.2011.09.010 PubMedCentralPubMedCrossRefGoogle Scholar
  57. 57.
    Ringholz GM, Appel SH, Bradshaw M, Cooke NA, Mosnik DM, Schulz PE (2005) Prevalence and patterns of cognitive impairment in sporadic ALS. Neurology 65:586–590. doi:10.1212/01.wnl.0000172911.39167.b6 PubMedCrossRefGoogle Scholar
  58. 58.
    Sampathu DM, Neumann M, Kwong LK, Chou TT, Micsenyi M, Truax A 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. doi:10.2353/ajpath.2006.060438 PubMedCrossRefGoogle Scholar
  59. 59.
    Simon-Sanchez J, Dopper EG, Cohn-Hokke PE, Hukema RK, Nicolaou N, Seelaar H et al (2012) The clinical and pathological phenotype of C9ORF72 hexanucleotide repeat expansions. Brain 135:723–735. doi:10.1093/brain/awr353 PubMedCrossRefGoogle Scholar
  60. 60.
    Snowden JS, Rollinson S, Thompson JC, Harris JM, Stopford CL, Richardson AM et al (2012) Distinct clinical and pathological characteristics of frontotemporal dementia associated with C9ORF72 mutations. Brain 135:693–708. doi:10.1093/brain/awr355 PubMedCrossRefGoogle Scholar
  61. 61.
    Stewart H, Rutherford NJ, Briemberg H, Krieger C, Cashman N, Fabros M et al (2012) Clinical and pathological features of amyotrophic lateral sclerosis caused by mutation in the C9ORF72 gene on chromosome 9p. Acta Neuropathol 123:409–417. doi:10.1007/s00401-011-0937-5 PubMedCentralPubMedCrossRefGoogle Scholar
  62. 62.
    Treusch S, Cyr DM, Lindquist S (2009) Amyloid deposits: protection against toxic protein species? Cell Cycle 8:1668–1674PubMedCrossRefGoogle Scholar
  63. 63.
    Troakes C, Maekawa S, Wijesekera L, Rogelj B, Siklos L, Bell C et al (2012) An MND/ALS phenotype associated with C9orf72 repeat expansion: abundant p62-positive, TDP-43-negative inclusions in cerebral cortex, hippocampus and cerebellum but without associated cognitive decline. Neuropathology 32:505–514. doi:10.1111/j.1440-1789.2011.01286.x PubMedCrossRefGoogle Scholar
  64. 64.
    Uryu K, Nakashima-Yasuda H, Forman MS, Kwong LK, Clark CM, Grossman M et al (2008) Concomitant TAR-DNA-binding protein 43 pathology is present in Alzheimer disease and corticobasal degeneration but not in other tauopathies. J Neuropathol Exp Neurol 67:555–564. doi:10.1097/NEN.0b013e31817713b5 PubMedCentralPubMedCrossRefGoogle Scholar
  65. 65.
    van Blitterswijk M, DeJesus-Hernandez M, Rademakers R (2012) How do C9ORF72 repeat expansions cause amyotrophic lateral sclerosis and frontotemporal dementia: can we learn from other noncoding repeat expansion disorders? Curr Opin Neurol 25:689–700. doi:10.1097/WCO.0b013e32835a3efb PubMedCrossRefGoogle Scholar
  66. 66.
    Wojciechowska M, Krzyzosiak WJ (2011) Cellular toxicity of expanded RNA repeats: focus on RNA foci. Hum Mol Genet 20:3811–3821. doi:10.1093/hmg/ddr299 PubMedCrossRefGoogle Scholar
  67. 67.
    Xi Z, Zinman L, Moreno D, Schymick J, Liang Y, Sato C et al (2013) Hypermethylation of the CpG Island near the G4C2 repeat in ALS with a C9orf72 expansion. Am J Hum Genet 92:981–989. doi:10.1016/j.ajhg.2013.04.017 PubMedCentralPubMedCrossRefGoogle Scholar
  68. 68.
    Xu Z, Poidevin M, Li X, Li Y, Shu L, Nelson DL et al (2013) Expanded GGGGCC repeat RNA associated with amyotrophic lateral sclerosis and frontotemporal dementia causes neurodegeneration. Proc Natl Acad Sci USA 110:7778–7783. doi:10.1073/pnas.1219643110 PubMedCrossRefGoogle Scholar
  69. 69.
    Zu T, Gibbens B, Doty NS, Gomes-Pereira M, Huguet A, Stone MD et al (2011) Non-ATG-initiated translation directed by microsatellite expansions. Proc Natl Acad Sci USA 108:260–265. doi:10.1073/pnas.1013343108 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Ian R. A. Mackenzie
    • 1
  • Petra Frick
    • 2
  • Manuela Neumann
    • 2
    • 3
  1. 1.Department of PathologyUniversity of British Columbia and Vancouver General HospitalVancouverCanada
  2. 2.DZNEGerman Center for Neurodegenerative DiseasesTübingenGermany
  3. 3.Department of NeuropathologyUniversity of TübingenTübingenGermany

Personalised recommendations