Acta Neuropathologica

, Volume 138, Issue 5, pp 795–811 | Cite as

C9orf72 intermediate repeats are associated with corticobasal degeneration, increased C9orf72 expression and disruption of autophagy

  • Christopher P. Cali
  • Maribel Patino
  • Yee Kit Tai
  • Wan Yun Ho
  • Catriona A. McLean
  • Christopher M. Morris
  • William W. Seeley
  • Bruce L. Miller
  • Carles Gaig
  • Jean Paul G. Vonsattel
  • Charles L. WhiteIII
  • Sigrun Roeber
  • Hans Kretzschmar
  • Juan C. Troncoso
  • Claire Troakes
  • Marla Gearing
  • Bernardino Ghetti
  • Vivianna M. Van Deerlin
  • Virginia M.-Y. Lee
  • John Q. Trojanowski
  • Kin Y. Mok
  • Helen Ling
  • Dennis W. Dickson
  • Gerard D. Schellenberg
  • Shuo-Chien Ling
  • Edward B. LeeEmail author
Original Paper


Microsatellite repeat expansion disease loci can exhibit pleiotropic clinical and biological effects depending on repeat length. Large expansions in C9orf72 (100s–1000s of units) are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). However, whether intermediate expansions also contribute to neurodegenerative disease is not well understood. Several studies have identified intermediate repeats in Parkinson’s disease patients, but the association was not found in autopsy-confirmed cases. We hypothesized that intermediate C9orf72 repeats are a genetic risk factor for corticobasal degeneration (CBD), a neurodegenerative disease that can be clinically similar to Parkinson’s but has distinct tau protein pathology. Indeed, intermediate C9orf72 repeats were significantly enriched in autopsy-proven CBD (n = 354 cases, odds ratio = 3.59, p = 0.00024). While large C9orf72 repeat expansions are known to decrease C9orf72 expression, intermediate C9orf72 repeats result in increased C9orf72 expression in human brain tissue and CRISPR/cas9 knockin iPSC-derived neural progenitor cells. In contrast to cases of FTD/ALS with large C9orf72 expansions, CBD with intermediate C9orf72 repeats was not associated with pathologic RNA foci or dipeptide repeat protein aggregates. Knock-in cells with intermediate repeats exhibit numerous changes in gene expression pathways relating to vesicle trafficking and autophagy. Additionally, overexpression of C9orf72 without the repeat expansion leads to defects in autophagy under nutrient starvation conditions. These results raise the possibility that therapeutic strategies to reduce C9orf72 expression may be beneficial for the treatment of CBD.


Neurodegeneration Corticobasal degeneration C9orf72 repeat expansion Parkinsonism Autophagy 



We acknowledge the contributions of the Los Angeles VA Hospital (University of California Los Angeles) and the Harvard Brain Tissue Resource Center (McLean Hospital) for contributing cases to this study. This study was supported by grants from the NIH (R01 NS095793, E.B.L.; R25 GM071745, M.P.; P01 AG017586, E.B.L., V.M.V.D, V.M.-Y.L, J.Q.T., G.S.; P30 AG010124, E.B.L., V.M.V.D, V.M.-Y.L, J.Q.T.; P30 AG10133, B.G.; UG3 NS104095, D.W.D.; U54 NS100693, D.W.D., G.S.; P30 AG012300 C.L.W.; P50 AG023501 and P01 AG019724 W.W.S., B.L.M.; P50 NS038377 and P50 AG05146 J.C.T.; P50 AG025688 M.G.), CurePSP (D.W.D.), the Tau Consortium (D.W.D. and W.W.S.), CBD Solutions (H.L. and K.Y.M.), National Medical Research Council, Singapore (NMRC/OFIRG/0001/2016 and NMRC/OFIRG/0042/2017 to S.C.L.), Ministry of Education, Singapore (MOE2016-T2-1-024 to S.C.L), the Reta Lila Weston Trust (K.Y.M.), the Bluefield Project to Cure FTD (W.W.S.), the UK Medical Research Council (G0400074 to C.M.M.), NIHR Newcastle Biomedical Research Center (C.M.M.), the Alzheimer’s Society and Alzheimer’s Research UK as part of the Brains for Dementia Research project (C.M.M.). The London Neurodegenerative Diseases Brain Bank receives funding from the UK Medical Research Council (MR/L016397/1) and as part of the Brains for Dementia Research programme, jointly funded by Alzheimer’s Research UK and the Alzheimer’s Society. We would also like to acknowledge Beth Dombroski, and EunRan Suh for their assistance, and the patients and families without which this research would not be possible.

Author contributions

EBL and S-CL conceived and designed this study. CPC performed RNA and protein expression experiments in patient brain and iPSCs. MP performed repeat size and risk allele genotyping. YKT, WYH and S-CL performed C9orf72 overexpression autophagy experiments. FH, WT, CMM, WWS, BLM, CG, JPGV, CLW, FMB, SR, HK, JCT, CT, MD, BG, VMVD, VMYL, JQT, KYM, HL, DWD, and GDS performed neuropathology analysis and provided DNA samples. CPC and EBL wrote the manuscript and all authors approved the final manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare no competing interests.

Supplementary material

401_2019_2045_MOESM1_ESM.pdf (1.3 mb)
Supplementary material 1 (PDF 1325 kb)
401_2019_2045_MOESM2_ESM.csv (1.7 mb)
Supplementary material 2 (CSV 1699 kb)


  1. 1.
    Akimoto C, Forsgren L, Linder J, Birve A, Backlund I, Andersson J et al (2013) No GGGGCC-hexanucleotide repeat expansion in C9ORF72 in parkinsonism patients in Sweden. Amyotroph Lateral Scler Front Degener 14:26–29. CrossRefGoogle Scholar
  2. 2.
    Amick J, Tharkeshwar AK, Amaya C, Ferguson SM (2018) WDR41 supports lysosomal response to changes in amino acid availability. Mol Biol Cell 29:2213–2227. CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Antonelli M, Barilà D, Manic G, Brandi R, Sambucci M, Arisi I et al (2017) ATM kinase sustains breast cancer stem-like cells by promoting ATG4C expression and autophagy. Oncotarget 8:21692–21709. CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Aoki Y, Manzano R, Lee Y, Dafinca R, Aoki M, Douglas AGL et al (2017) C9orf72 and RAB7L1 regulate vesicle trafficking in amyotrophic lateral sclerosis and frontotemporal dementia. Brain 140:887–897. CrossRefPubMedGoogle Scholar
  5. 5.
    Armstrong MJ, Litvan I, Lang AE, Bak TH, Bhatia KP, Borroni B et al (2013) Criteria for the diagnosis of corticobasal degeneration. Neurology 80:496–503. CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Ash PEA, 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. CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Beck J, Poulter M, Hensman D, Rohrer JD, Mahoney CJ, Adamson G et al (2013) Large C9orf72 hexanucleotide repeat expansions are seen in multiple neurodegenerative syndromes and are more frequent than expected in the UK population. Am J Hum Genet 92:345–353. CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    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. CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Bender R, Lange S (2001) Adjusting for multiple testing—when and how? J Clin Epidemiol 54:343–349. CrossRefPubMedGoogle Scholar
  10. 10.
    van Blitterswijk M, DeJesus-Hernandez M, Niemantsverdriet E, Murray ME, Heckman MG, Diehl NN et al (2013) Association between repeat sizes and clinical and pathological characteristics in carriers of C9ORF72 repeat expansions (Xpansize-72): a cross-sectional cohort study. Lancet Neurol 12:978–988. CrossRefPubMedGoogle Scholar
  11. 11.
    Boeve BF, Maraganore DM, Parisi JE, Ahlskog JE, Graff-Radford N, Caselli RJ et al (1999) Pathologic heterogeneity in clinically diagnosed corticobasal degeneration. Neurology 53:795–800. CrossRefPubMedGoogle Scholar
  12. 12.
    Burberry A, Suzuki N, Wang JY, Moccia R, Mordes DA, Stewart MH et al (2016) Loss-of-function mutations in the C9ORF72 mouse ortholog cause fatal autoimmune disease. Sci Transl Med 8:93. CrossRefGoogle Scholar
  13. 13.
    Cannas A, Solla P, Borghero G, Floris GL, Chio A, Mascia MM et al (2015) C9ORF72 intermediate repeat expansion in patients affected by atypical Parkinsonian syndromes or parkinson’s disease complicated by psychosis or dementia in a Sardinian population. J Neurol 262:2498–2503. CrossRefPubMedGoogle Scholar
  14. 14.
    Chambers SM, Fasano CA, Papapetrou EP, Tomishima M, Sadelain M, Studer L (2009) Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nat Biotechnol 27:275–280. CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Chew J, Gendron TF, Prudencio M, Sasaguri H, Zhang YJ, Castanedes-Casey M et al (2015) C9ORF72 repeat expansions in mice cause TDP-43 pathology, neuronal loss, and behavioral deficits. Science 348:1151–1154CrossRefGoogle Scholar
  16. 16.
    Chitiprolu M, Jagow C, Tremblay V, Bondy-Chorney E, Paris G, Savard A et al (2018) A complex of C9ORF72 and p62 uses arginine methylation to eliminate stress granules by autophagy. Nat Commun 9:2794. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Ciura S, Sellier C, Campanari ML, Charlet-Berguerand N, Kabashi E (2016) The most prevalent genetic cause of ALS-FTD, C9orf72 synergizes the toxicity of ATXN2 intermediate polyglutamine repeats through the autophagy pathway. Autophagy 12:1406–1408. CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Corbier C, Sellier C (2016) C9ORF72 is a GDP/GTP exchange factor for Rab8 and Rab39 and regulates autophagy. Small GTPases. CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Dejesus-hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ et al (2011) Expanded GGGGCC hexanucleotide repeat in non-coding region of C9ORF72 causes chromosome 9p-linked frontotemporal dementia and amyotrophic lateral sclerosis. Neuron 72:245–256. CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    DeJesus-Hernandez M, Rayaprolu S, Soto-Ortolaza AI, Rutherford NJ, Heckman MG, Traynor S et al (2013) Analysis of the C9orf72 repeat in Parkinson’s disease, essential tremor and restless legs syndrome. Parkinsonism Relat Disord 19:198–201. CrossRefPubMedGoogle Scholar
  21. 21.
    Dickson DW, Bergeron C, Chin SS, Duyckaerts C, Horoupian D, Ikeda K et al (2002) Office of rare diseases neuropathologic criteria for corticobasal degeneration. J Neuropathol Exp Neurol 61:935–946. CrossRefPubMedGoogle Scholar
  22. 22.
    Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S et al (2013) STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29:15–21. CrossRefPubMedGoogle Scholar
  23. 23.
    Dobson-Stone C, Hallupp M, Loy CT, Thompson EM, Haan E, Sue CM et al (2013) C9ORF72 repeat expansion in australian and spanish frontotemporal dementia patients. PLoS One. CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Donnelly CJ, Zhang P, 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. CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Elden AC, Kim H, Hart MP, Chen-plotkin AS, Johnson S, Fang X et al (2011) Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature 466:1069–1075. CrossRefGoogle Scholar
  26. 26.
    Farg MA, Sundaramoorthy V, Sultana JM, Yang S, Atkinson RAK, Levina V et al (2014) C9ORF72, implicated in amyotrophic lateral sclerosis and frontotemporal dementia, regulates endosomal trafficking. Hum Mol Genet 23:3579–3595. CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Frick P, Sellier C, Mackenzie IRA, Cheng C, Tahraoui-bories J, Martinat C et al (2018) Novel antibodies reveal presynaptic localization of C9orf72 protein and reduced protein levels in C9orf72 mutation carriers. Acta Neuropathol Commun 6:1–17. CrossRefGoogle Scholar
  28. 28.
    Gijselinck I, Van Mossevelde S, van der Zee J, Sieben A, Engelborghs S, De Bleecker J et al (2015) The C9orf72 repeat size correlates with onset age of disease, DNA methylation and transcriptional downregulation of the promoter. Mol Psychiatry 21:1–13. CrossRefGoogle Scholar
  29. 29.
    Hagerman RJ, Leehey M, Heinrichs W, Tassone F, Wilson R, Hills J et al (2001) Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X. Neurology 57:127–130. CrossRefPubMedGoogle Scholar
  30. 30.
    Harms MB, Neumann D, Benitez BA, Cooper B, Carrell D, Racette BA et al (2013) Parkinson disease is not associated with C9ORF72 repeat expansions. Neurobiol Aging 34:1519. CrossRefPubMedGoogle Scholar
  31. 31.
    Ho WY, Tai YK, Chang J-C, Liang J, Tyan S-H, Chen S et al (2019) The ALS-FTD-linked gene product, C9orf72, regulates neuronal morphogenesis via autophagy. Autophagy. CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Jiao B, Guo J, Wang Y, Yan X, Zhou L, Liu X et al (2013) C9orf72 mutation is rare in Alzheimer’s disease, Parkinson’s disease, and essential tremor in China. Front Cell Neurosci 7:164. CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Kouri N, Murray ME, Hassan A, Rademakers R, Uitti RJ, Boeve BF et al (2011) Neuropathological features of corticobasal degeneration presenting as corticobasal syndrome or Richardson syndrome. Brain 134:3264–3275. CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Kouri N, Ross OA, Dombroski B, Younkin CS, Serie DJ, Soto-Ortolaza A et al (2015) Genome-wide association study of corticobasal degeneration identifies risk variants shared with progressive supranuclear palsy. Nat Commun 6:7247. CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Lee EB, Lee VMY, Trojanowski JQ (2012) Gains or losses: molecular mechanisms of TDP43-mediated neurodegeneration. Nat Rev Neurosci 13:38–50. CrossRefGoogle Scholar
  36. 36.
    Lee YB, Chen HJ, Peres JN, Gomez-Deza J, Attig J, Štalekar M et al (2013) Hexanucleotide repeats in ALS/FTD form length-dependent RNA Foci, sequester RNA binding proteins, and are neurotoxic. Cell Rep 5:1178–1186. CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Lesage S, Le Ber I, Condroyer C, Broussolle E, Gabelle A, Thobois S et al (2013) C9orf72 repeat expansions are a rare genetic cause of parkinsonism. Brain 136:385–391. CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Levine TP, Daniels RD, Gatta AT, Wong LH, Hayes MJ (2013) The product of C9orf72, a gene strongly implicated in neurodegeneration, is structurally related to DENN Rab-GEFs. Bioinformatics 29:499–503. CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Ling H, O’Sullivan SS, Holton JL, Revesz T, Massey LA, Williams DR et al (2010) Does corticobasal degeneration exist? A clinicopathological re-evaluation. Brain 133:2045–2057. CrossRefPubMedGoogle Scholar
  40. 40.
    Litvan I, Agid Y, Goetz C, Jankovic J, Wenning GK, Brandel JP et al (1997) Accuracy of the clinical diagnosis of corticobasal degeneration: a clinicopathologic study. Neurology 48:119–125. CrossRefPubMedGoogle Scholar
  41. 41.
    Liu EY, Russ J, Wu K, Neal D, Suh E, McNally AG et al (2014) C9orf72 hypermethylation protects against repeat expansion-associated pathology in ALS/FTD. Acta Neuropathol 128:525–541. CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Liu Y, Pattamatta A, Zu T, Reid T, Bardhi O, Borchelt DR et al (2016) C9orf72 BAC mouse model with motor deficits and neurodegenerative features of ALS/FTD. Neuron 90:521–534. CrossRefPubMedGoogle Scholar
  43. 43.
    Liu Y, Wang T, Ji YJ, Johnson K, Liu H, Johnson K et al (2018) A C9orf72-CARM1 axis regulates lipid metabolism under glucose starvation-induced nutrient stress. Genes Dev 32:1380–1397. CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Lonsdale J, Thomas J, Salvatore M, Phillips R, Lo E, Shad S et al (2013) The Genotype-Tissue Expression (GTEx) project. Nat Genet 45:580–585. CrossRefGoogle Scholar
  45. 45.
    Love MI, Huber W, Anders S (2014) Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol 15:550. CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Maguire JA, Gagne AL, Jobaliya CD, Gandre-Babbe S, Gadue P, French DL (2016) Generation of human control iPS cell line CHOPWT10 from healthy adult peripheral blood mononuclear cells. Stem Cell Res 16:338–341. CrossRefPubMedGoogle Scholar
  47. 47.
    Maharjan N, Künzli C, Buthey K, Saxena S (2017) C9ORF72 regulates stress granule formation and its deficiency impairs stress granule assembly, hypersensitizing cells to stress. Mol Neurobiol 54:3062–3077. CrossRefPubMedGoogle Scholar
  48. 48.
    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. CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Majounie E, Renton AE, Mok K, Dopper EGP, Waite A, Rollinson S et al (2012) Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study. Lancet Neurol 11:323–330. CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Martin M (2011) Cutadapt removes adapter sequences from high-throughput sequencing reads. EMBnet J 17:10–12CrossRefGoogle Scholar
  51. 51.
    Mauthe M, Orhon I, Rocchi C, Zhou X, Luhr M, Hijlkema K-J et al (2018) Chloroquine inhibits autophagic flux by decreasing autophagosome–lysosome fusion. Autophagy 14:1435–1455. CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    McMillan CT, Russ J, Wood EM, Irwin DJ, Grossman M, Mccluskey L et al (2015) C9orf72 promoter hypermethylation is neuroprotective: neuroimaging and neuropathologic evidence. Neurology 84:1622–1630. CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Mok K, Traynor BJ, Schymick J, Tienari PJ, Laaksovirta H, Peuralinna T et al (2012) The chromosome 9 ALS and FTD locus is probably derived from a single founder. Neurobiol Aging 33:209.e3–209.e8. CrossRefGoogle Scholar
  54. 54.
    Nakatogawa H, Ichimura Y, Ohsumi Y (2007) Atg8, a ubiquitin-like protein required for autophagosome formation, mediates membrane tethering and hemifusion. Cell 130:165–178. CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Nassif M, Woehlbier U, Manque PA (2017) The enigmatic role of C9ORF72 in autophagy. Front Neurosci 11:1–10. CrossRefGoogle Scholar
  56. 56.
    Nuytemans K, Bademci G, Kohli MM, Beecham GW, Wang L, Young JI et al (2013) C9orf72 intermediate repeat copies are a significant risk factor for parkinson disease. Ann Hum Genet 77:351–363. CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Nuytemans K, Inchausti V, Beecham GW, Wang L, Dickson DW, Trojanowski JQ et al (2014) Absence of C9ORF72 expanded or intermediate repeats in autopsy-confirmed Parkinson’s disease. Mov Disord 29:827–830. CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    O’Rourke JG, Bogdanik L, Yáñez A, Lall D, Wolf AJ, Muhammad AKMG et al (2016) C9orf72 is required for proper macrophage and microglial function in mice. Science 351:1324–1329. CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Ran FA, Hsu PD, Wright J, Agarwala V, Scott DA, Zhang F (2013) Genome engineering using the CRISPR-Cas9 system. Nat Protoc 8:2281–2308. CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Renton A, Majounie E, Waite A, Simón-Sánchez 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. CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Russ J, Liu EY, Wu K, Neal D, Suh ER, Irwin DJ et al (2015) Hypermethylation of repeat expanded C9orf72 is a clinical and molecular disease modifier. Acta Neuropathol 129:39–52. CrossRefPubMedGoogle Scholar
  62. 62.
    Sanpei K, Takano H, Igarashi S, Sato T, Oyake M, Sasaki H et al (1996) Identification of the spinocerebellar ataxia type 2 gene using a direct identification of repeat expansion and cloning technique, DIRECT. Nat Genet 14:277–284. CrossRefPubMedGoogle Scholar
  63. 63.
    Sareen D, O’Rourke JG, Meera P, Muhammad AKMG, Grant S, Simpkinson M et al (2013) Targeting RNA foci in iPSC-derived motor neurons from ALS patients with a C9ORF72 repeat expansion. Sci Transl Med 5:208ra149. CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Schottlaender LV, Polke JM, Ling H, MacDoanld ND, Tucci A, Nanji T et al (2015) The analysis of C9orf72 repeat expansions in a large series of clinically and pathologically diagnosed cases with atypical parkinsonism. Neurobiol Aging 36:1221.e1–1221.e6. CrossRefGoogle Scholar
  65. 65.
    Sellier C, Campanari M-L, Julie Corbier C, Gaucherot A, Kolb-Cheynel I, Oulad-Abdelghani M et al (2016) Loss of C9ORF72 impairs autophagy and synergizes with polyQ Ataxin-2 to induce motor neuron dysfunction and cell death. EMBO J 35:1–22. CrossRefGoogle Scholar
  66. 66.
    Shi Y, Kirwan P, Livesey FJ (2012) Directed differentiation of human pluripotent stem cells to cerebral cortex neurons and neural networks. Nat Protoc 7:1836–1846. CrossRefGoogle Scholar
  67. 67.
    Shi Y, Lin S, Staats KA, Li Y, Chang W-H, Hung S-T et al (2018) Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons. Nat Med. CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Snowden JS, Rollinson S, Thompson JC, Harris JM, Stopford CL, Richardson AMT et al (2012) Distinct clinical and pathological characteristics of frontotemporal dementia associated with C9ORF72 mutations. Brain 135:693–708. CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Stenmark H (2009) Rab GTPases as coordinators of vesicle traffic. Nat Rev Mol Cell Biol 10:513–525. CrossRefPubMedGoogle Scholar
  70. 70.
    Suh ER, Lee EB, Neal D, Wood EM, Toledo JB, Rennert L et al (2015) Semi-automated quantification of C9orf72 expansion size reveals inverse correlation between hexanucleotide repeat number and disease duration in frontotemporal degeneration. Acta Neuropathol 130:363–372. CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Sun Y, Chen Y, Zhang J, Cao L, He M, Liu X et al (2017) TMEM74 promotes tumor cell survival by inducing autophagy via interactions with ATG16L1 and ATG9A. Cell Death Dis 8:e3031. CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Tanida I, Minematsu-Ikeguchi N, Ueno T, Kominami E (2005) Lysosomal turnover, but not a cellular level, of endogenous LC3 is a marker for autophagy. Autophagy 1:84–91. CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Theuns J, Verstraeten A, Sleegers K, Wauters E, Gijselinck I, Smolders S et al (2014) Global investigation and meta-analysis of the C9orf72 (G4C2)n repeat in Parkinson disease. Neurology 83:1906–1913. CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Ugolino J, Ji YJ, Conchina K, Chu J, Nirujogi RS, Pandey A et al (2016) Loss of C9orf72 enhances autophagic activity via deregulated mTOR and TFEB signaling. PLoS Genet 1:1. CrossRefGoogle Scholar
  75. 75.
    Verkerk AJMH, Pieretti M, Sutcliffe JS, Fu YH, Kuhl DPA, Pizzuti A et al (1991) Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell 65:905–914. CrossRefPubMedGoogle Scholar
  76. 76.
    Viodé A, Fournier C, Camuzat A, Fenaille F, Latouche M, Elahi F et al (2018) New antibody-free mass spectrometry-based quantification reveals that C9ORF72 long protein isoform is reduced in the frontal cortex of hexanucleotide-repeat expansion carriers. Front Neurosci 12:1–11. CrossRefGoogle Scholar
  77. 77.
    Waite AJ, Bäumer D, East S, Neal J, Morris HR, Ansorge O et al (2014) Reduced C9orf72 protein levels in frontal cortex of amyotrophic lateral sclerosis and frontotemporal degeneration brain with the C9ORF72 hexanucleotide repeat expansion. Neurobiol Aging 35:1779.e5–1779.e13. CrossRefGoogle Scholar
  78. 78.
    Wang N, Tan HY, Li S, Feng Y (2017) Atg9b deficiency suppresses autophagy and potentiates endoplasmic reticulum stress-associated hepatocyte apoptosis in hepatocarcinogenesis. Theranostics 7:2325–2338. CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Webster CP, Smith EF, Bauer CS, Moller A, Hautbergue GM, Ferraiuolo L et al (2016) The C9orf72 protein interacts with Rab1a and the ULK1 complex to regulate initiation of autophagy. EMBO J 35:1656–1676. CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Xi Z, Zinman L, Grinberg Y, Moreno D, Sato C, Bilbao JM et al (2012) Investigation of C9orf72 in 4 neurodegenerative disorders. Arch Neurol 69:1583. CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    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. CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Xie Z, Nair U, Klionsky DJ (2008) Atg8 controls phagophore expansion during autophagosome formation. Mol Biol Cell 19:3290–3298. CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Yang M, Liang C, Swaminathan K, Herrlinger S, Lai F, Shiekhattar R et al (2016) A C9ORF72/SMCR1-containing complex regulates ULK1 and plays a dual role in autophagy. Sci Adv. CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Yeh TH, Lai SC, Weng YH, Kuo HC, Wu-Chou YH, Huang CL et al (2013) Screening for C9orf72 repeat expansions in parkinsonian syndromes. Neurobiol Aging 34:1311.e3–1311.e4. CrossRefGoogle Scholar
  85. 85.
    Yu C, Wang L, Lv B, Lu Y, Zeng L, Chen Y et al (2008) TMEM74, a lysosome and autophagosome protein, regulates autophagy. Biochem Biophys Res Commun 369:622–629. CrossRefPubMedGoogle Scholar
  86. 86.
    van der Zee J, Gijselinck I, Dillen L, Van Langenhove T, Theuns J, Engelborghs S et al (2013) A Pan-European STUDY of the C9orf72 repeat associated with FTLD: geographic prevalence, genomic instability, and intermediate repeats. Hum Mutat 34:363–373. CrossRefPubMedGoogle Scholar
  87. 87.
    Zhou J, Tan SH, Nicolas V, Bauvy C, Di Yang N, Zhang J et al (2013) Activation of lysosomal function in the course of autophagy via mTORC1 suppression and autophagosome–lysosome fusion. Cell Res 23:508–523. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Christopher P. Cali
    • 1
  • Maribel Patino
    • 1
  • Yee Kit Tai
    • 2
  • Wan Yun Ho
    • 2
  • Catriona A. McLean
    • 3
  • Christopher M. Morris
    • 4
  • William W. Seeley
    • 5
    • 6
  • Bruce L. Miller
    • 5
  • Carles Gaig
    • 7
  • Jean Paul G. Vonsattel
    • 8
  • Charles L. WhiteIII
    • 9
  • Sigrun Roeber
    • 10
  • Hans Kretzschmar
    • 10
  • Juan C. Troncoso
    • 11
  • Claire Troakes
    • 12
  • Marla Gearing
    • 13
  • Bernardino Ghetti
    • 14
  • Vivianna M. Van Deerlin
    • 15
  • Virginia M.-Y. Lee
    • 15
  • John Q. Trojanowski
    • 15
  • Kin Y. Mok
    • 16
    • 17
  • Helen Ling
    • 18
  • Dennis W. Dickson
    • 19
  • Gerard D. Schellenberg
    • 20
  • Shuo-Chien Ling
    • 2
  • Edward B. Lee
    • 1
    Email author
  1. 1.Translational Neuropathology Research Laboratory, Department of Pathology and Laboratory MedicineUniversity of PennsylvaniaPhiladelphiaUSA
  2. 2.Department of PhysiologyNational University of SingaporeSingaporeSingapore
  3. 3.Department of Anatomical PathologyAlfred Health and Victorian Brain Bank, Florey NeurosciencesParkvilleAustralia
  4. 4.Newcastle Brain Tissue Resource, Edwardson BuildingNewcastle UniversityNewcastle upon TyneUK
  5. 5.Department of NeurologyUniversity of CaliforniaSan FranciscoUSA
  6. 6.Department of PathologyUniversity of CaliforniaSan FranciscoUSA
  7. 7.Universitat de Barcelona Hospital Clínic and Banc de Teixits NeurològicsBarcelonaSpain
  8. 8.Columbia University, NY Brain BankNew YorkUSA
  9. 9.University of Texas Southwestern Medical CenterDallasUSA
  10. 10.Institute for Neuropathology and Prion Research and Brain Net GermanyLudwig-Maximilians-UniversitätMunichGermany
  11. 11.Department of PathologyJohns Hopkins UniversityBaltimoreUSA
  12. 12.London Neurodegenerative Diseases Brain Bank, Institute of Psychiatry, Psychology and Neuroscience, King’s College LondonLondonUK
  13. 13.Department of PathologyEmory UniversityAtlantaUSA
  14. 14.Department of Pathology and Laboratory MedicineIndiana University School of MedicineIndianapolisUSA
  15. 15.Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory MedicineUniversity of PennsylvaniaPhiladelphiaUSA
  16. 16.Department of Neurodegenerative DiseaseUniversity College London Queen Square Institute of NeurologyLondonUK
  17. 17.Division of Life Science, State Key Laboratory of Molecular Neuroscience and Molecular Neuroscience CenterThe Hong Kong University of Science and TechnologyKowloonChina
  18. 18.Reta Lila Weston Institute of Neurological StudiesUniversity College London Institute of NeurologyLondonUK
  19. 19.Department of NeuroscienceMayo ClinicJacksonvilleUSA
  20. 20.Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory MedicineUniversity of PennsylvaniaPhiladelphiaUSA

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