RAN translation at CGG repeats induces ubiquitin proteasome system impairment in models of fragile X-associated tremor ataxia syndrome

Human Molecular Genetics

Volumn 24, Issue 15, 2015, Pages 4317-4326

  Oh, Seok Yoon ^a   He, Fang ^a   Krans, Amy ^a   Frazer, Michelle ^a   Taylor Paul, J ^b   Paulson, Henry L ^a   Todd, Peter K ^a,c  

^a UNIVERSITY OF MICHIGAN MEDICAL SCHOOL   (United States)

^b ST JUDE CHILDREN S RESEARCH HOSPITAL   (United States)

^c VA ANN ARBOR HEALTHCARE SYSTEM   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMINO ACID DERIVATIVE; CYSTEINYLGLYCYLGLYCINE; FRAGILE X MENTAL RETARDATION PROTEIN; GLYCINE DERIVATIVE; HEAT SHOCK PROTEIN 70; POLYGLYCINE; PROTEASOME; RAN PROTEIN; RNA; UNCLASSIFIED DRUG; DROSOPHILA PROTEIN; FMR1 PROTEIN, DROSOPHILA; FMR1 PROTEIN, HUMAN; UBIQUITIN;

ANIMAL MODEL; ARTICLE; ATAXIA; AUTOPHAGY; CONTROLLED STUDY; CYTOTOXICITY; DEGENERATIVE DISEASE; DROSOPHILA; FEMALE; FRAGILE X ASSOCIATED TREMOR ATAXIA SYNDROME; FRAGILE X SYNDROME; GENE EXPRESSION; GENE EXPRESSION PROFILING; GENE FUNCTION; GENE INTERACTION; GENE REPRESSION; HELA CELL LINE; HUMAN; HUMAN CELL; IN VITRO STUDY; IN VIVO STUDY; MAMMAL CELL; NONHUMAN; PATHOGENESIS; PRIORITY JOURNAL; PROTEIN HOMEOSTASIS; PROTEIN INDUCTION; PROTEIN QUALITY; REPORTER GENE; RNA TRANSLATION; TRINUCLEOTIDE REPEAT; ANIMAL; DISEASE MODEL; DROSOPHILA MELANOGASTER; GENETICS; METABOLISM; MOUSE; PATHOLOGY; TRANSGENIC ANIMAL; TREMOR;

ANIMALS; ANIMALS, GENETICALLY MODIFIED; ATAXIA; DISEASE MODELS, ANIMAL; DROSOPHILA MELANOGASTER; DROSOPHILA PROTEINS; FRAGILE X MENTAL RETARDATION PROTEIN; FRAGILE X SYNDROME; HUMANS; MICE; NEURODEGENERATIVE DISEASES; PROTEASOME ENDOPEPTIDASE COMPLEX; TREMOR; TRINUCLEOTIDE REPEAT EXPANSION; UBIQUITIN;

EID: 84940061997     PISSN: 09646906     EISSN: 14602083     Source Type: Journal    
DOI: 10.1093/hmg/ddv165     Document Type: Article

References (75)

1. Hagerman, R.J., Leehey, M., Heinrichs, W., Tassone, F., Wilson, R., Hills, J., Grigsby, J., Gage, B. and Hagerman, P.J. (2001) Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X. Neurology, 57, 127-130.
2. Jacquemont, S., Hagerman, R.J., Leehey, M.A., Hall, D.A., Levine, R.A., Brunberg, J.A., Zhang, L., Jardini, T., Gane, L.W., Harris, S.W. et al. (2004) Penetrance of the fragile X-associated tremor/ataxia syndrome in a premutation carrier population. JAMA, 291, 460-469.
3. Berry-Kravis, E., Abrams, L., Coffey, S.M., Hall, D.A., Greco, C., Gane, L.W., Grigsby, J., Bourgeois, J.A., Finucane, B., Jacquemont, S. et al. (2007) Fragile X-associated tremor/ataxia syndrome:clinical features, genetics, and testing guidelines. Mov. Disord., 22, 2018-2030, quiz 2140.
4. Jacquemont, S., Hagerman, R.J., Leehey, M., Grigsby, J., Zhang, L., Brunberg, J.A., Greco, C., Des Portes, V., Jardini, T., Levine, R. et al. (2003) Fragile X premutation tremor/ataxia syndrome:molecular, clinical, and neuroimaging correlates. Am. J. Hum. Genet., 72, 869-878.
5. Pieretti, M., Zhang, F.P., Fu, Y.H., Warren, S.T., Oostra, B.A., Caskey, C.T. and Nelson, D.L. (1991) Absence of expression of the FMR-1 gene in fragile X syndrome. Cell, 66, 817-822.
6. Kremer, E.J., Pritchard, M., Lynch, M., Yu, S., Holman, K., Baker, E., Warren, S.T., Schlessinger, D., Sutherland, G.R. and Richards, R.I. (1991) Mapping ofDNA instability at the fragile X to a trinucleotide repeat sequence p(CCG)n. Science, 252, 1711-1714.
7. Verkerk, A.J., Pieretti, M., Sutcliffe, J.S., Fu, Y.H., Kuhl, D.P., Pizzuti, A., Reiner, O., Richards, S., Victoria, M.F., Zhang, F.P. 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.
8. Vincent, A., Heitz, D., Petit, C., Kretz, C., Oberle, I. and Mandel, J.L. (1991) Abnormal pattern detected in fragile-X patients by pulsed-field gel electrophoresis. Nature, 349, 624-626.
9. Yu, S., Pritchard, M., Kremer, E., Lynch, M., Nancarrow, J., Baker, E., Holman, K., Mulley, J., Warren, S., Schlessinger, D. et al. (1991) Fragile X genotype characterized by an unstable region of DNA. Science, 252, 1179-1181.
10. Krueger, D.D. and Bear, M.F. (2011) Toward fulfilling the promise of molecular medicine in fragile X syndrome. Annu. Rev. Med., 62, 411-429.
11. Tassone, F., Hagerman, R.J., Taylor, A.K., Gane, L.W., Godfrey, T.E. and Hagerman, P.J. (2000) Elevated levels of FMR1 mRNA in carrier males: a newmechanism of involvement in the fragile-X syndrome. Am. J. Hum. Genet., 66, 6-15.
12. Tassone, F., Beilina, A., Carosi, C., Albertosi, S., Bagni, C., Li, L., Glover, K., Bentley, D. and Hagerman, P.J. (2007) Elevated FMR1 mRNA in premutation carriers is due to increased transcription. RNA, 13, 555-562.
13. Tassone, F., Iwahashi, C. and Hagerman, P.J. (2004) FMR1 RNA within the intranuclear inclusions of fragile X-associated tremor/ataxia syndrome (FXTAS). RNA Biol., 1, 103-105.
14. Todd, P.K., Oh, S.Y., Krans, A., Pandey, U.B., Di Prospero, N.A., Min, K.T., Taylor, J.P. and Paulson, H.L. (2010) Histone deacetylases suppress CGG repeat-induced neurodegeneration via transcriptional silencing in models of fragile X tremor ataxia syndrome. PLoS Genet., 6, e1001240.
15. Usdin, K., Hayward, B.E., Kumari, D., Lokanga, R.A., Sciascia, N. and Zhao, X.N. (2014) Repeat-mediated genetic and epigenetic changes at the FMR1 locus in the Fragile X-related disorders. Front. Genet., 5, 226.
16. Hagerman, P. (2013) Fragile X-associated tremor/ataxia syndrome (FXTAS): pathology and mechanisms. Acta Neuropathol., 126, 1-19.
17. Jin, P., Zarnescu, D.C., Zhang, F., Pearson, C.E., Lucchesi, J.C., Moses, K. and Warren, S.T. (2003) RNA-mediated neurodegeneration caused by the fragile X premutation rCGG repeats in Drosophila. Neuron, 39, 739-747.
18. Jin, P., Duan, R., Qurashi, A., Qin, Y., Tian, D., Rosser, T.C., Liu, H., Feng, Y. andWarren, S.T. (2007) Pur alpha binds to rCGG repeats and modulates repeat-mediated neurodegeneration in a Drosophila model of fragile X tremor/ataxia syndrome. Neuron, 55, 556-564.
19. Sofola, O.A., Jin, P., Qin, Y., Duan, R., Liu, H., de Haro, M., Nelson, D.L. and Botas, J. (2007) RNA-binding proteins hnRNP A2/B1 and CUGBP1 suppress fragile X CGG premutation repeat-induced neurodegeneration in a Drosophila model of FXTAS. Neuron, 55, 565-571.
20. Sellier, C., Usdin, K., Pastori, C., Peschansky, V.J., Tassone, F. and Charlet-Berguerand, N. (2014) The multiple molecular facets of fragile X-associated tremor/ataxia syndrome. J. Neurodev. Disord., 6, 23.
21. Sellier, C., Rau, F., Liu, Y., Tassone, F., Hukema, R.K., Gattoni, R., Schneider, A., Richard, S., Willemsen, R., Elliott, D.J. et al. (2010) Sam68 sequestration and partial loss of function are associated with splicing alterations in FXTAS patients. EMBO J., 29, 1248-1261.
22. Thornton, C.A. (2014) Myotonic dystrophy. Neurol. Clin., 32, 705-719, viii.
23. Mohan, A., Goodwin, M. and Swanson, M.S. (2014) RNA-protein interactions in unstable microsatellite diseases. Brain. Res., 1584, 3-14.
24. Cooper, T.A., Wan, L. and Dreyfuss, G. (2009) RNA and disease. Cell, 136, 777-793.
25. Kanadia, R.N., Shin, J., Yuan, Y., Beattie, S.G., Wheeler, T.M., Thornton, C.A. and Swanson, M.S. (2006) Reversal of RNA missplicing and myotonia after muscleblind overexpression in a mouse poly(CUG) model for myotonic dystrophy. Proc. Natl Acad. Sci. USA, 103, 11748-11753.
26. de Haro, M., Al-Ramahi, I., De Gouyon, B., Ukani, L., Rosa, A., Faustino, N.A., Ashizawa, T., Cooper, T.A. and Botas, J. (2006) MBNL1 and CUGBP1 modify expanded CUG-induced toxicity in a Drosophila model of myotonic dystrophy type 1. Hum. Mol. Genet., 15, 2138-2145.
27. Sellier, C., Freyermuth, F., Tabet, R., Tran, T., He, F., Ruffenach, F., Alunni, V., Moine, H., Thibault, C., Page, A. et al. (2013) Sequestration of DROSHA and DGCR8 by expanded CGG RNA repeats alters microRNA processing in fragile X-associated tremor/ataxia syndrome. Cell Rep., 3, 869-880.
28. Todd, P.K., Oh, S.Y., Krans, A., He, F., Sellier, C., Frazer, M., Renoux, A.J., Chen, K.C., Scaglione, K.M., Basrur, V. et al. (2013) CGG repeat-associated translation mediates neurodegeneration in fragile X tremor ataxia syndrome. Neuron, 78, 440-455.
29. Zu, T., Gibbens, B., Doty, N.S., Gomes-Pereira, M., Huguet, A., Stone, M.D., Margolis, J., Peterson, M., Markowski, T.W., Ingram, M.A. et al. (2010) Non-ATG-initiated translation directed by microsatellite expansions. Proc. Natl Acad. Sci. USA, 108, 260-265.
30. Ash, P.E., Bieniek, K.F., Gendron, T.F., Caulfield, T., Lin, W.L., Dejesus-Hernandez, M., van Blitterswijk, M.M., Jansen-West, K., Paul, J.W. III, Rademakers, R. et al. (2013) Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. Neuron, 77, 639-646.
31. Mori, K., Weng, S.M., Arzberger, T., May, S., Rentzsch, K., Kremmer, E., Schmid, B., Kretzschmar, H.A., Cruts, M., Van Broeckhoven, C. et al. (2013) The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science, 339, 1335-1338.
32. Mori, K., Arzberger, T., Grasser, F.A., Gijselinck, I., May, S., Rentzsch, K., Weng, S.M., Schludi, M.H., van der Zee, J., Cruts, M. et al. (2013) Bidirectional transcripts of the expanded C9orf72 hexanucleotide repeat are translated into aggregating dipeptide repeat proteins. Acta Neuropathol., 126, 881-893.
33. Zu, T., Liu, Y., Banez-Coronel, M., Reid, T., Pletnikova, O., Lewis, J., Miller, T.M., Harms, M.B., Falchook, A.E., Subramony, S.H. et al. (2013) RAN proteins and RNA foci from antisense transcripts in C9ORF72 ALS and frontotemporal dementia. Proc. Natl Acad. Sci. USA, 110, E4968-E4977.
34. Gendron, T.F., Bieniek, K.F., Zhang, Y.J., Jansen-West, K., Ash, P.E., Caulfield, T., Daughrity, L., Dunmore, J.H., Castanedes-Casey, M., Chew, J. 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.
35. Kearse, M.G. and Todd, P.K. (2014) Repeat-associated non-AUG translation and its impact in neurodegenerative disease. Neurotherapeutics, 11, 721-731.
36. Todd, P.K. and Paulson, H.L. (2010) RNA-mediated neurodegeneration in repeat expansion disorders. Ann. Neurol., 67, 291-300.
37. Handa, V., Goldwater, D., Stiles, D., Cam, M., Poy, G., Kumari, D. and Usdin, K. (2005) Long CGG-repeat tracts are toxic to human cells: implications for carriers of Fragile X premutation alleles. FEBS Lett., 579, 2702-2708.
38. Iwahashi, C.K., Yasui, D.H., An, H.J., Greco, C.M., Tassone, F., Nannen, K., Babineau, B., Lebrilla, C.B., Hagerman, R.J. and Hagerman, P.J. (2006) Protein composition of the intranuclear inclusions of FXTAS. Brain, 129, 256-271.
39. Garcia-Arocena, D., Yang, J.E., Brouwer, J.R., Tassone, F., Iwahashi, C., Berry-Kravis, E.M., Goetz, C.G., Sumis, A.M., Zhou, L., Nguyen, D.V. et al. (2010) Fibroblast phenotype in male carriers of FMR1 premutation alleles. Hum. Mol. Genet., 19, 299-312.
40. Nedelsky, N.B., Todd, P.K. and Taylor, J.P. (2008) Autophagy and the ubiquitin-proteasome system: collaborators in neuroprotection. Biochim. Biophys. Acta., 1782, 691-699.
41. Pandey, U.B., Nie, Z., Batlevi, Y., McCray, B.A., Ritson, G.P., Nedelsky, N.B., Schwartz, S.L., DiProspero, N.A., Knight, M.A., Schuldiner, O. et al. (2007) HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS. Nature, 447, 859-863.
42. Pickford, F., Masliah, E., Britschgi, M., Lucin, K., Narasimhan, R., Jaeger, P.A., Small, S., Spencer, B., Rockenstein, E., Levine, B. et al. (2008) The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice. J. Clin. Invest., 118, 2190-2199.
43. Ross, C.A. and Pickart, C.M. (2004) The ubiquitin-proteasome pathway in Parkinson's disease and other neurodegenerative diseases. Trends Cell. Biol., 14, 703-711.
44. Sontag, E.M., Vonk, W.I. and Frydman, J. (2014) Sorting out the trash: the spatial nature of eukaryotic protein quality control. Curr. Opin. Cell. Biol., 26, 139-146.
45. Warrick, J.M., Chan, H.Y., Gray-Board, G.L., Chai, Y., Paulson, H.L. and Bonini, N.M. (1999) Suppression of polyglutaminemediated neurodegeneration in Drosophila by the molecular chaperone HSP70. Nat. Genet., 23, 425-428.
46. Auluck, P.K., Chan, H.Y., Trojanowski, J.Q., Lee, V.M. and Bonini, N.M. (2002) Chaperone suppression of alpha-synuclein toxicity in a Drosophila model for Parkinson's disease. Science, 295, 865-868.
47. Chan, H.Y., Warrick, J.M., Andriola, I., Merry, D. and Bonini, N. M. (2002) Genetic modulation of polyglutamine toxicity by protein conjugation pathways in Drosophila. Hum. Mol. Genet., 11, 2895-2904.
48. Chartier, A., Benoit, B. and Simonelig, M. (2006) A Drosophila model of oculopharyngeal muscular dystrophy reveals intrinsic toxicity of PABPN1. EMBO J., 25, 2253-2262.
49. Chan, W.M., Tsoi, H., Wu, C.C., Wong, C.H., Cheng, T.C., Li, H. Y., Lau, K.F., Shaw, P.C., Perrimon, N. and Chan, H.Y. (2011) Expanded polyglutamine domain possesses nuclear export activity which modulates subcellular localization and toxicity of polyQ disease protein via exportin-1. Hum. Mol. Genet., 20, 1738-1750.
50. Du, G., Liu, X., Chen, X., Song, M., Yan, Y., Jiao, R. andWang, C. C. (2010) Drosophila histone deacetylase 6 protects dopaminergic neurons against {alpha}-synuclein toxicity by promoting inclusion formation. Mol. Biol. Cell, 21, 2128-2137.
51. Estes, P.S., Boehringer, A., Zwick, R., Tang, J.E., Grigsby, B. and Zarnescu, D.C. (2011) Wild-type and A315T mutant TDP-43 exert differential neurotoxicity in a Drosophila model of ALS. Hum. Mol. Genet., 20, 2308-2321.
52. Fernandez-Funez, P., Nino-Rosales, M.L., de Gouyon, B., She, W.C., Luchak, J.M., Martinez, P., Turiegano, E., Benito, J., Capovilla, M., Skinner, P.J. et al. (2000) Identification of genes that modify ataxin-1-induced neurodegeneration. Nature, 408, 101-106.
53. Ghosh, S. and Feany, M.B. (2004) Comparison of pathways controlling toxicity in the eye and brain in Drosophila models of human neurodegenerative diseases. Hum. Mol. Genet., 13, 2011-2018.
54. Mallik, M. and Lakhotia, S.C. (2010) Improved activities of CREB binding protein, heterogeneous nuclear ribonucleoproteins and proteasome following downregulation of noncoding hsromega transcripts help suppress poly(Q) pathogenesis in fly models. Genetics, 184, 927-945.
55. Miguel, L., Avequin, T., Delarue, M., Feuillette, S., Frebourg, T., Campion, D. and Lecourtois, M. (2012) Accumulation of insoluble forms of FUS protein correlates with toxicity in Drosophila. Neurobiol. Aging, 33, 1008 e1001-1015.
56. Shieh, S.Y. and Bonini, N.M. (2011) Genes and pathways affected by CAG-repeat RNA-based toxicity in Drosophila. Hum. Mol. Genet., 20, 4810-4821.
57. Vo, S.H., Butzlaff, M., Pru, S.K., Ni Charthaigh, R.A., Karsten, P., Lankes, A., Hamm, S., Simons, M., Adryan, B., Schulz, J.B. et al. (2012) Large-scale screen for modifiers of ataxin-3-derived polyglutamine-induced toxicity in Drosophila. PLoS One, 7, e47452.
58. Shulman, J.M. and Feany, M.B. (2003) Genetic modifiers of tauopathy in Drosophila. Genetics, 165, 1233-1242.
59. Warrick, J.M., Morabito, L.M., Bilen, J., Gordesky-Gold, B., Faust, L.Z., Paulson, H.L. and Bonini, N.M. (2005) Ataxin-3 suppresses polyglutamine neurodegeneration in Drosophila by a ubiquitin-associated mechanism. Mol. Cell, 18, 37-48.
60. Ziviani, E., Tao, R.N. and Whitworth, A.J. (2010) Drosophila parkin requires PINK1 for mitochondrial translocation and ubiquitinates mitofusin. Proc. Natl Acad. Sci. USA, 107, 5018-5023.
61. Covi, J.A., Belote, J.M. and Mykles, D.L. (1999) Subunit compositions and catalytic properties of proteasomes fromdevelopmental temperature-sensitive mutants of Drosophila melanogaster. Arch. Biochem. Biophys., 368, 85-97.
62. Lin, Y., Tang, C., He, H. and Duan, R. (2013) Activation ofmTOR ameliorates fragile X premutation rCGG repeat-mediated neurodegeneration. PLoS One, 8, e62572.
63. Berger, Z., Ravikumar, B., Menzies, F.M., Oroz, L.G., Underwood, B.R., Pangalos, M.N., Schmitt, I., Wullner, U., Evert, B. O., O'Kane, C.J. et al. (2006) Rapamycin alleviates toxicity of different aggregate-prone proteins. Hum. Mol. Genet., 15, 433-442.
64. Dantuma, N.P., Lindsten, K., Glas, R., Jellne, M. and Masucci, M.G. (2000) Short-lived green fluorescent proteins for quantifying ubiquitin/proteasome-dependent proteolysis in living cells. Nat. Biotechnol., 18, 538-543.
65. Arocena, D.G., Iwahashi, C.K., Won, N., Beilina, A., Ludwig, A. L., Tassone, F., Schwartz, P.H. and Hagerman, P.J. (2005) Induction of inclusion formation and disruption of lamin A/C structure by premutation CGG-repeat RNA in human cultured neural cells. Hum. Mol. Genet., 14, 3661-3671.
66. Williams, A.J. and Paulson, H.L. (2008) Polyglutamine neurodegeneration:protein misfolding revisited. Trends Neurosci., 31, 521-528.
67. Cuervo, A.M., Stefanis, L., Fredenburg, R., Lansbury, P.T. and Sulzer, D. (2004) Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science, 305, 1292-1295.
68. Ravikumar, B., Duden, R. and Rubinsztein, D.C. (2002) Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy. Hum. Mol. Genet., 11, 1107-1117.
69. Ravikumar, B., Stewart, A., Kita, H., Kato, K., Duden, R. and Rubinsztein, D.C. (2003) Raised intracellular glucose concentrations reduce aggregation and cell death caused by mutant huntingtin exon 1 by decreasing mTOR phosphorylation and inducing autophagy. Hum. Mol. Genet., 12, 985-994.
70. Sarkar, S., Davies, J.E., Huang, Z., Tunnacliffe, A. and Rubinsztein, D.C. (2007) Trehalose, a novelmTOR-independent autophagy enhancer, accelerates the clearance of mutant huntingtin and alpha-synuclein. J. Biol. Chem., 282, 5641-5652.
71. May, S., Hornburg, D., Schludi, M.H., Arzberger, T., Rentzsch, K., Schwenk, B.M., Grasser, F.A., Mori, K., Kremmer, E., Banzhaf-Strathmann, J. et al. (2014) C9orf72 FTLD/ALS-associated Gly-Ala dipeptide repeat proteins cause neuronal toxicity and Unc119 sequestration. Acta Neuropathol., 128, 485-503.
72. Mizielinska, S., Gronke, S., Niccoli, T., Ridler, C.E., Clayton, E. L., Devoy, A., Moens, T., Norona, F.E., Woollacott, I.O., Pietrzyk, J. et al. (2014) C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins. Science, 345, 1192-1194.
73. Zhang, Y.J., Jansen-West, K., Xu, Y.F., Gendron, T.F., Bieniek, K. F., Lin, W.L., Sasaguri, H., Caulfield, T., Hubbard, J., Daughrity, L. et al. (2014) Aggregation-prone c9FTD/ALS poly(GA) RANtranslated proteins cause neurotoxicity by inducing ER stress. Acta Neuropathol., 128, 505-524.
74. Kwon, I., Xiang, S., Kato, M., Wu, L., Theodoropoulos, P., Wang, T., Kim, J., Yun, J., Xie, Y. and McKnight, S.L. (2014) Poly-dipeptides encoded by the C9orf72 repeats bind nucleoli, impede RNA biogenesis, and kill cells. Science, 345, 1139-1145.
75. Su, Z., Zhang, Y., Gendron, T.F., Bauer, P.O., Chew, J., Yang, W. Y., Fostvedt, E., Jansen-West, K., Belzil, V.V., Desaro, P. et al. (2014) Discovery of a biomarker and lead small molecules to target r(GGGGCC)-associated defects in c9FTD/ALS. Neuron, 83, 1043-1050.