The role of dipeptide repeats in C9ORF72-related ALS-FTD

Frontiers in Molecular Neuroscience

Volumn 10, Issue , 2017, Pages

  Freibaum, Brian D ^a   Taylor, J Paul ^a,b  

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

^b HOWARD HUGHES MEDICAL INSTITUTE   (United States)

Author keywords

Amyotrophic lateral sclerosis; C9orf72; Dipeptide repeat; Frontotemporal dementia; Liquid liquid phase separation; Nuclear pore; Nucleocytoplasmic transport; RNA metabolism

Indexed keywords

ALANINE; ARGININE; GLYCINE; PROLINE;

AMYOTROPHIC LATERAL SCLEROSIS; CHROMOSOME 9; CYTOTOXICITY; DEGENERATIVE DISEASE; DIPEPTIDE REPEAT; DROSOPHILA; FRONTOTEMPORAL DEMENTIA; HUMAN; IMMUNOHISTOCHEMISTRY; MOUSE; NERVE DEGENERATION; NONHUMAN; NUCLEOTIDE REPEAT; OPEN READING FRAME; PATHOGENESIS; PROTEIN EXPRESSION; REVIEW; RNA METABOLISM; RNA SEQUENCE;

EID: 85014023200     PISSN: 16625099     EISSN: None     Source Type: Journal    
DOI: 10.3389/fnmol.2017.00035     Document Type: Review

References (70)

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.
2. Ash, P. E., Bieniek, K. F., Gendron, T. F., Caulfield, T., Lin, W. L., 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.
3. Baborie, A., Griffiths, T. D., Jaros, E., Perry, R., McKeith, I. G., Burn, D. J., et al. (2015). Accumulation of dipeptide repeat proteins predates that of TDP-43 in frontotemporal lobar degeneration associated with hexanucleotide repeat expansions in C9ORF72 gene. Neuropathol. Appl. Neurobiol. 41, 601–612. doi: 10.1111/nan.12178.
4. Belzil, V. V., Bauer, P. O., Prudencio, M., Gendron, T. F., Stetler, C. T., Yan, I. K., 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.
5. Boeynaems, S., Bogaert, E., Michiels, E., Gijselinck, I., Sieben, A., Jovicic, A., et al. (2016). Drosophila screen connects nuclear transport genes to DPR pathology in c9ALS/FTD. Sci. Rep. 6:20877. doi: 10.1038/srep20877.
6. Boisvert, F. M., van Koningsbruggen, S., Navascués, J., and Lamond, A. I. (2007). The multifunctional nucleolus. Nat. Rev. Mol. Cell Biol. 8, 574–585. doi: 10.1038/nrm2184.
7. Brangwynne, C. P., Tompa, P., and Pappu, R. V. (2015). Polymer physics of intracellular phase transitions. Nat. Phys. 11, 899–904. doi: 10.1038/nphys3532.
8. Chang, Y.-J., Jeng, U. S., Chiang, Y. L., Hwang, I. S., and Chen, Y. R. (2016). The glycine-alanine dipeptide repeat from C9orf72 hexanucleotide expansions forms toxic amyloids possessing cell-to-cell transmission properties. J. Biol. Chem. 291, 4903–4911. doi: 10.1074/jbc.m115.694273.
9. Chew, J., Gendron, T. F., Prudencio, M., Sasaguri, H., Zhang, Y. J., Castanedes-Casey, M., et al. (2015). Neurodegeneration. C9ORF72 repeat expansions in mice cause TDP-43 pathology, neuronal loss, and behavioral deficits. Science 348, 1151–1154. doi: 10.1126/science.aaa9344.
10. Cleary, J. D., and Ranum, L. P. (2013). Repeat-associated non-ATG (RAN) translation in neurological disease. Hum. Mol. Genet. 22, R45–R51. doi: 10.1093/hmg/ddt371.
11. Conlon, E. G., Lu, L., Sharma, A., Yamazaki, T., Tang, T., Shneider, N. A., et al. (2016). The C9ORF72 GGGGCC expansion forms RNA G-quadruplex inclusions and sequesters hnRNP H to disrupt splicing in ALS patient brains. Elife 5:e17820. doi: 10.7554/elife.17820.
12. Cooper-Knock, J., Hewitt, C., Highley, J. R., 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.
13. Davidson, Y. S., Barker, H., Robinson, A. C., Thompson, J. C., Harris, J., Troakes, C., et al. (2014). Brain distribution of dipeptide repeat proteins in frontotemporal lobar degeneration and motor neurone disease associated with expansions in C9ORF72. Acta Neuropathol. Commun. 2:70. doi: 10.1186/2051-5960-2-70.
14. DeJesus-Hernandez, M., Mackenzie, I. R., Boeve, B. F., Boxer, A. L., Baker, M., Rutherford, N. J., 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.
15. Donnelly, C. J., Zhang, P. W., Pham, J. T., Haeusler, A. R., Mistry, N. A., 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.
16. Edbauer, D., and Haass, C. (2016). An amyloid-like cascade hypothesis for C9orf72 ALS/FTD. Curr. Opin. Neurobiol. 36, 99–106. doi: 10.1016/j.conb.2015. 10.009.
17. Fratta, P., Mizielinska, S., Nicoll, A. J., Zloh, M., Fisher, E. M., Parkinson, G., et al. (2012). C9orf72 hexanucleotide repeat associated with amyotrophic lateral sclerosis and frontotemporal dementia forms RNA G-quadruplexes. Sci. Rep. 2:1016. doi: 10.1038/srep01016.
18. Freibaum, B. D., Lu, Y., Lopez-Gonzalez, R., Kim, N. C., Almeida, S., Lee, K. H., et al. (2015). GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport. Nature 525, 129–133. doi: 10.1038/nature 14974.
19. Gendron, T. F., Bieniek, K. F., Zhang, Y. J., Jansen-West, K., Ash, P. E., 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.
20. 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.
21. Gomez-Deza, J., Lee, Y. B., Troakes, C., Nolan, M., Al-Sarraj, S., Gallo, J. M., et al. (2015). Dipeptide repeat protein inclusions are rare in the spinal cord and almost absent from motor neurons in C9ORF72 mutant amyotrophic lateral sclerosis and are unlikely to cause their degeneration. Acta Neuropathol. Commun. 3:38. doi: 10.1186/s40478-015-0218-y.
22. Haeusler, A. R., Donnelly, C. J., Periz, G., Simko, E. A., Shaw, P. G., Kim, M. S., et al. (2014). C9orf72 nucleotide repeat structures initiate molecular cascades of disease. Nature 507, 195–200. doi: 10.1038/nature13124.
23. Hsiung, G. Y., DeJesus-Hernandez, M., Feldman, H. H., 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.
24. Huntley, M. A., and Golding, G. B. (2002). Simple sequences are rare in the protein data bank. Proteins 48, 134–140. doi: 10.1002/prot.10150.
25. Jiang, J., Zhu, Q., Gendron, T. F., Saberi, S., McAlonis-Downes, M., Seelman, A., et al. (2016). Gain of toxicity from ALS/FTD-linked repeat expansions in C9ORF72 is alleviated by antisense oligonucleotides targeting GGGGCC-containing RNAs. Neuron 90, 535–550. doi: 10.1016/j.neuron.2016.04.006.
26. Jovičić, A., Mertens, J., Boeynaems, S., Bogaert, E., Chai, N., Yamada, S. B., et al. (2015). Modifiers of C9orf72 dipeptide repeat toxicity connect nucleocytoplasmic transport defects to FTD/ALS. Nat. Neurosci. 18, 1226–1229. doi: 10.1038/nn.4085.
27. Kanekura, K., Yagi, T., Cammack, A. J., Mahadevan, J., Kuroda, M., Harms, M. B., et al. (2016). Poly-dipeptides encoded by the C9ORF72 repeats block global protein translation. Hum. Mol. Genet. 25, 1803–1813. doi: 10.1093/hmg/ddw052.
28. Knobel, K. M., Davis, W. S., Jorgensen, E. M., and Bastiani, M. J. (2001). UNC-119 suppresses axon branching in C. elegans. Development 128, 4079–4092.
29. Koppers, M., Blokhuis, A. M., Westeneng, H. J., Terpstra, M. L., Zundel, C. A., Vieira De Sá, R., et al. (2015). C9orf72 ablation in mice does not cause motor neuron degeneration or motor deficits. Ann. Neurol. 78, 426–438. doi: 10.1002/ana.24453.
30. Kwon, I., Xiang, S., Kato, M., Wu, L., Theodoropoulos, P., Wang, T., et al. (2014). Poly-dipeptides encoded by the C9orf72 repeats bind nucleoli, impede RNA biogenesis and kill cells. Science 345, 1139–1145. doi: 10.1126/science.1254917.
31. Lee, K. H., Zhang, P., Kim, H. J., Mitrea, D. M., Sarkar, M., Freibaum, B. D., et al. (2016). C9orf72 dipeptide repeats impair the assembly, dynamics, and function of membrane-less organelles. Cell 167, 774.e17–788.e17. doi: 10.1016/j.cell. 2016.10.002.
32. Lin, Y., Mori, E., Kato, M., Xiang, S., Wu, L., Kwon, I., et al. (2016). Toxic PR poly-dipeptides encoded by the C9orf72 repeat expansion target LC domain polymers. Cell 167, 789.e12–802.e12. doi: 10.1016/j.cell.2016.10.003.
33. Liu, Y., Pattamatta, A., Zu, T., Reid, T., Bardhi, O., Borchelt, D. R., et al. (2016). C9orf72 BAC mouse model with motor deficits and neurodegenerative features of ALS/FTD. Neuron 90, 521–534. doi: 10.1016/j.neuron.2016. 04.005.
34. Lopez-Gonzalez, R., Lu, Y., Gendron, T. F., Karydas, A., Tran, H., Yang, D., et al. (2016). Poly(GR) in C9ORF72-Related ALS/FTD compromises mitochondrial function and increases oxidative stress and DNA damage in iPSC-derived motor neurons. Neuron 92, 383–391. doi: 10.1016/j.neuron.2016.09.015.
35. Mackenzie, I. R., 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.
36. Mahoney, C. J., Beck, J., Rohrer, J. D., 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.
37. Majounie, E., Renton, A. E., Mok, K., Dopper, E. G., 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. doi: 10.1016/S1474-4422(12)70043-1.
38. Mann, D. M., Rollinson, S., Robinson, A., Bennion Callister, J., Thompson, J. C., Snowden, J. S., 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 Neuropathol. Commun. 1:68. doi: 10.1186/2051-5960-1-68.
39. May, S., Hornburg, D., Schludi, M. H., Arzberger, T., Rentzsch, K., Schwenk, B. M., et al. (2014). C9orf72 FTLD/ALS-associated Gly-Ala dipeptide repeat proteins cause neuronal toxicity and Unc119 sequestration. Acta Neuropathol. 128, 485–503. doi: 10.1007/s00401-014-1329-4.
40. Mizielinska, S., Grönke, S., Niccoli, T., Ridler, C. E., Clayton, E. L., Devoy, A., et al. (2014). C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins. Science 345, 1192–1194. doi: 10.1126/science. 1256800.
41. Mizielinska, S., Lashley, T., Norona, F. E., Clayton, E. L., Ridler, C. E., 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.
42. Molliex, A., Temirov, J., Lee, J., Coughlin, M., Kanagaraj, A. P., Kim, H. J., et al. (2015). Phase separation by low complexity domains promotes stress granule assembly and drives pathological fibrillization. Cell 163, 123–133. doi: 10.1016/j.cell.2015.09.015.
43. Mori, K., Arzberger, T., Grässer, F. A., Gijselinck, I., May, S., Rentzsch, K., et al. (2013a). 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.
44. Mori, K., Lammich, S., Mackenzie, I. R., Forné, I., Zilow, S., Kretzschmar, H., et al. (2013b). 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.
45. Mori, K., Weng, S. M., Arzberger, T., May, S., Rentzsch, K., Kremmer, E., et al. (2013c). The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science 339, 1335–1338. doi: 10.1126/science. 1232927.
46. Neumann, M., Sampathu, D. M., Kwong, L. K., Truax, A. C., Micsenyi, M. C., Chou, T. T., et al. (2006). Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314, 130–133. doi: 10.1126/science.1134108.
47. O’Rourke, J. G., Bogdanik, L., Muhammad, A. K., Gendron, T. F., Kim, K. J., Austin, A., et al. (2015). C9orf72 BAC transgenic mice display typical pathologic features of ALS/FTD. Neuron 88, 892–901. doi: 10.1016/j.neuron.2015.10.027.
48. O’Rourke, J. G., Bogdanik, L., Yáñez, A., Lall, D., Wolf, A. J., Muhammad, A. K., et al. (2016). C9orf72 is required for proper macrophage and microglial function in mice. Science 351, 1324–1329. doi: 10.1126/science.aaf1064.
49. Peters, O. M., Cabrera, G. T., Tran, H., Gendron, T. F., Mckeon, J. E., Metterville, J., et al. (2015). Human C9ORF72 hexanucleotide expansion reproduces RNA foci and dipeptide repeat proteins but not neurodegeneration in BAC transgenic mice. Neuron 88, 902–909. doi: 10.1016/j.neuron.2015.11.018.
50. Reddy, K., Zamiri, B., Stanley, S. Y., Macgregor, R. B. Jr., and Pearson, C. E. (2013). The disease-associated r(GGGGCC)n repeat from the C9orf72 gene forms tract length-dependent uni- and multimolecular RNA G-quadruplex structures. J. Biol. Chem. 288, 9860–9866. doi: 10.1074/jbc.c113.452532.
51. Renton, A. E., Majounie, E., Waite, A., Simón-Sánchez, J., Rollinson, S., Gibbs, J. R., 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.
52. Rossi, S., Serrano, A., Gerbino, V., Giorgi, A., Di Francesco, L., Nencini, M., et al. (2015). Nuclear accumulation of mRNAs underlies G4C2-repeat-induced translational repression in a cellular model of C9orf72 ALS. J. Cell Sci. 128, 1787–1799. doi: 10.1242/jcs.165332.
53. Schipper, L. J., Raaphorst, J., Aronica, E., Baas, F., De Haan, R., De Visser, M., et al. (2016). Prevalence of brain and spinal cord inclusions, including dipeptide repeat proteins, in patients with the C9ORF72 hexanucleotide repeat expansion: a systematic neuropathological review. Neuropathol. Appl. Neurobiol. 42, 547–560. doi: 10.1111/nan.12284.
54. Schludi, M. H., May, S., Grässer, F. A., Rentzsch, K., Kremmer, E., Küpper, C., et al. (2015). Distribution of dipeptide repeat proteins in cellular models and C9orf72 mutation cases suggests link to transcriptional silencing. Acta Neuropathol. 130, 537–555. doi: 10.1007/s00401-015-1450-z.
55. Schmidt, H. B., and Görlich, D. (2016). Transport selectivity of nuclear pores, phase separation, and membraneless organelles. Trends Biochem. Sci. 41, 46–61. doi: 10.1016/j.tibs.2015.11.001.
56. n poly-dipeptides encoded by the C9orf72 repeat expansion block nuclear import and export. Proc. Natl. Acad. Sci. U S A doi: 10.1073/pnas.1620293114 [Epub ahead of print].
57. Tao, Z., Wang, H., Xia, Q., Li, K., Li, K., Jiang, X., et al. (2015). Nucleolar stress and impaired stress granule formation contribute to C9orf72 RAN translation-induced cytotoxicity. Hum. Mol. Genet. 24, 2426–2441. doi: 10.1093/hmg/ddv005.
58. Taylor, J. P., Brown, R. H., and Cleveland, D. W. (2016). Decoding ALS from genes to mechanism. Nature 539, 197–206. doi: 10.1038/nature20413.
59. Troakes, C., Maekawa, S., Wijesekera, L., Rogelj, B., Siklós, 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.
60. Uversky, V. N. (2002). Natively unfolded proteins: a point where biology waits for physics. Protein Sci. 11, 739–756. doi: 10.1110/ps.4210102.
61. Vatsavayai, S. C., Yoon, S. J., Gardner, R. C., Gendron, T. F., Vargas, J. N., Trujillo, A., et al. (2016). Timing and significance of pathological features in C9orf72 expansion-associated frontotemporal dementia. Brain 139, 3202–3216. doi: 10.1093/brain/aww250.
62. Wen, X., Tan, W., Westergard, T., Krishnamurthy, K., Markandaiah, S. S., Shi, Y., et al. (2014). Antisense proline-arginine RAN dipeptides linked to C9ORF72-ALS/FTD form toxic nuclear aggregates that initiate in vitro and in vivo neuronal death. Neuron 84, 1213–1225. doi: 10.1016/j.neuron.2014. 12.010.
63. Westergard, T., Jensen, B. K., Wen, X., Cai, J., Kropf, E., Iacovitti, L., et al. (2016). Cell-to-cell transmission of dipeptide repeat proteins linked to C9orf72-ALS/FTD. Cell Rep. 17, 645–652. doi: 10.1016/j.celrep.2016.09.032.
64. Yamakawa, M., Ito, D., Honda, T., Kubo, K., Noda, M., Nakajima, K., et al. (2015). Characterization of the dipeptide repeat protein in the molecular pathogenesis of c9FTD/ALS. Hum. Mol. Genet. 24, 1630–1645. doi: 10.1093/hmg/ddu576.
65. Yang, D., Abdallah, A., Li, Z., Lu, Y., Almeida, S., and Gao, F. B. (2015). FTD/ALS-associated poly(GR) protein impairs the Notch pathway and is recruited by poly(GA) into cytoplasmic inclusions. Acta Neuropathol. 130, 525–535. doi: 10.1007/s00401-015-1448-6.
66. Zhang, K., Donnelly, C. J., Haeusler, A. R., Grima, J. C., Machamer, J. B., Steinwald, P., et al. (2015). The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature 525, 56–61. doi: 10.1038/nature 14973.
67. Zhang, Y.-J., Gendron, T. F., Grima, J. C., Sasaguri, H., Jansen-West, K., Xu, Y. F., et al. (2016). C9ORF72 poly(GA) aggregates sequester and impair HR23 and nucleocytoplasmic transport proteins. Nat. Neurosci. 19, 668–677. doi: 10.1038/nn.4272.
68. Zhang, Y. J., Jansen-West, K., Xu, Y. F., Gendron, T. F., Bieniek, K. F., Lin, W. L., et al. (2014). Aggregation-prone c9FTD/ALS poly(GA) RAN-translated proteins cause neurotoxicity by inducing ER stress. Acta Neuropathol. 128, 505–524. doi: 10.1007/s00401-014-1336-5.
69. Zu, T., Gibbens, B., Doty, N. S., Gomes-Pereira, M., Huguet, A., Stone, M. D., et al. (2011). Non-ATG-initiated translation directed by microsatellite expansions. Proc. Natl. Acad. Sci. U S A 108, 260–265. doi: 10.1073/pnas.1013343108.
70. Zu, T., Liu, Y., Bañez-Coronel, M., Reid, T., Pletnikova, O., Lewis, J., et al. (2013). RAN proteins and RNA foci from antisense transcripts in C9ORF72 ALS and frontotemporal dementia. Proc. Natl. Acad. Sci. U S A 110, E4968–E4977. doi: 10.1073/pnas.1315438110.