C9orf72 amyotrophic lateral sclerosis and frontotemporal dementia: Gain or loss of function?

Current Opinion in Neurology

Volumn 27, Issue 5, 2014, Pages 515-523

  Mizielinska, Sarah ^a   Isaacs, Adrian M ^a  

^a UNIVERSITY COLLEGE LONDON   (United Kingdom)

Author keywords

Amyotrophic lateral sclerosis; C9orf72; Frontotemporal dementia; Gain or loss of function

Indexed keywords

ANTISENSE OLIGONUCLEOTIDE; DIPEPTIDE; PROTEIN AGGREGATE; RNA; C9ORF72 PROTEIN, HUMAN; PROTEIN; REPETITIVE DNA; UNTRANSLATED RNA;

AMYOTROPHIC LATERAL SCLEROSIS; AUTOPHAGY; CHROMOSOME 9; ENDOCYTOSIS; FRONTOTEMPORAL DEMENTIA; GAIN OF FUNCTION MUTATION; GENE TARGETING; HUMAN; LOSS OF FUNCTION MUTATION; MOTOR PERFORMANCE; NEUROPATHOLOGY; NONHUMAN; REVIEW; RNA SPLICING; BRAIN; CHEMISTRY; DRUG EFFECTS; GENETIC PREDISPOSITION; GENETICS; METABOLISM;

AMYOTROPHIC LATERAL SCLEROSIS; BRAIN; DNA REPEAT EXPANSION; FRONTOTEMPORAL DEMENTIA; GENETIC PREDISPOSITION TO DISEASE; HUMANS; OLIGONUCLEOTIDES, ANTISENSE; PROTEINS; RNA, UNTRANSLATED;

EID: 84909944879     PISSN: 13507540     EISSN: 14736551     Source Type: Journal    
DOI: 10.1097/WCO.0000000000000130     Document Type: Review

References (63)

1. Dejesus-Hernandez M, Mackenzie IR, Boeve BF, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 2011;72:245-256.
2. Renton AE, Majounie E, Waite A, et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 2011;72:257-268.
3. Lashley T, Hardy J, Isaacs AM. RANTing about C9orf72. Neuron 2013;77:597-598.
4. Gijselinck I, Van Langenhove T, Van Der ZJ, et al. 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 2012;11:54-65.
5. Fratta P, Poulter M, Lashley T, et al. Homozygosity for the C9orf72 GGGGCC repeat expansion in frontotemporal dementia. Acta Neuropathol 2013;126:401-409. First description of homozygous C9orf72 repeat expansion carrier.
6. Almeida S, Gascon E, Tran H, et al. Modeling key pathological features of frontotemporal dementia with C9ORF72 repeat expansion in iPSC-derivedhuman neurons. Acta Neuropathol 2013;126:385-399. First description of RNA foci and DPR protein in C9FTD patient-derived iPSC neurons.
7. Belzil VV, Bauer PO, Prudencio M, et al. Reduced C9orf72 gene expression in c9FTD/ALS is caused by histone trimethylation, an epigenetic event detectable in blood. Acta Neuropathol 2013;126:895-905. This article identifies histone methylation as a mechanism for reduction of C9orf72 transcription in C9FTD/ALS.
8. Donnelly CJ, Zhang PW, Pham JT, et al. RNA toxicity from the ALS/FTD C9ORF72 expansion is mitigated by antisense intervention. Neuron 2013;80:415-428. One of three articles showing therapeutic potential of ASOs in C9ALS/FTD patient-derived cells.
9. Waite AJ, Baumer D, East S, et al. Reduced C9orf72 protein levels in frontal cortex of amyotrophic lateral sclerosis and frontotemporal degeneration brain with the C9ORF72 hexanucleotide repeat expansion. Neurobiol Aging 2014;35:e5-13; 1779. First description of reduced C9orf72 protein in C9ALS/FTD patient tissue.
10. Xi Z, Zinman L, Moreno D, et al. Hypermethylation of the CpG island near the G4C2 repeat in ALS with a C9orf72 expansion. Am J Hum Genet 2013;92:981-989. First description of CpG island methylation as a mechanism for reduced C9orf72 transcription.
11. Liu EY, Russ J, Wu K, et al. C9orf72 hypermethylation protects against repeat expansion-associated pathology in ALS/FTD. Acta Neuropathol 2014; Epub 2014 May 8. This study found a correlation between methylation status and clinical phenotype, suggesting that hypermethylation and thus decreased C9orf72 is protective.
12. Farg MA, Sundaramoorthy V, Sultana JM, et al. C9ORF72, implicated in amytrophic lateral sclerosis and frontotemporal dementia, regulates endosomal trafficking. Hum Mol Genet 2014;23:3579-3595.
13. Levine TP, Daniels RD, Gatta AT, et al. The product of C9orf72, a gene strongly implicated in neurodegeneration, is structurally related to DENN Rab-GEFs. Bioinformatics 2013;29:499-503.
14. Zhang D, Iyer LM, He F, et al. Discovery of novel DENN proteins: implications for the evolution of eukaryotic intracellular membrane structures and human disease. Front Genet 2012;3:1-10; Article 283. doi:10.3389/fgene.2012.00283.
15. Ciura S, Lattante S, Le B I. Loss of function of C9orf72 causes motor deficits in a zebrafish model of amyotrophic lateral sclerosis. Ann Neurol 2013;74:180-187. First loss of C9orf72 function in zebrafish model.
16. Therrien M, Rouleau GA, Dion PA, et al. Deletion of C9ORF72 results inmotor neuron degeneration and stress sensitivity in C.elegans. PLoS One 2013;8:e83450. First loss of C9orf72 in Caenorhabditis elegans model.
17. Lagier-Tourenne C, Baughn M, Rigo F, et al. Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration. Proc Natl Acad Sci U S A 2013;110:E4530-E4539. One of three articles showing therapeutic potential of ASOs in C9FTD/ALS patient-derived cells, and one of the first descriptions of antisense RNA foci in C9FTD/ALS patient tissue.
18. Harms MB, Cady J, Zaidman C, et al. Lack of C9ORF72 coding mutations supports a gain of function for repeat expansions in amyotrophic lateral sclerosis. Neurobiol Aging 2013;34:2234-2239.
19. Mizielinska S, Lashley T, Norona FE, et al. C9orf72 frontotemporal lobar degeneration is characterised byfrequent neuronal sense and antisense RNA foci. Acta Neuropathol 2013;126:845-857. One of the first descriptions of antisense RNA foci in C9FTD/ALS patient tissue and also reports a correlation between RNA foci burden and clinical phenotypes, suggesting a role for RNA foci in C9FTD/ALS.
20. Gendron TF, Bieniek KF, Zhang YJ, et al. Antisense transcripts of the expanded C9ORF72 hexanucleotide repeat form nuclear RNA foci and undergo repeat-associated non-ATG translation in c9FTD/ALS. Acta Neuropathol 2013;126:829-844. One ofthe first descriptions ofantisense RNA foci and DPR proteininC9FTD/ALS patient tissue.
21. Zu T, Liu Y, Banez-Coronel M, et al. RAN proteins and RNA foci from antisense transcripts in C9ORF72 ALS and frontotemporal dementia. Proc Natl Acad Sci U S A 2013;110:E4968-4977. One ofthe first descriptions ofantisense RNA foci and DPR proteininC9FTD/ALS patient tissue and provides evidence for cellular toxicity of DPR proteins.
22. Sareen D, O'Rourke JG, Meera P, et al. Targeting RNA foci in iPSC-derived motor neurons from ALS patients with a C9ORF72 repeat expansion. Sci Transl Med 2013;5:208ra149. One of three articles showing therapeutic potential of ASOs in C9FTD/ALS patient-derived cells, and also reports sequestration of RNA-binding proteins into RNA foci.
23. Mori K, Lammich S, Mackenzie IR, et al. 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 2013;125:413-423. Identification of hnRNP A3 as a binding protein of expanded C9orf72 repeat RNA and its presence in a subset of neuronal inclusions.
24. Lee YB, Chen HJ, Peres JN, et al. Hexanucleotide repeats in ALS/FTD form length-dependent RNA foci, sequester RNA binding proteins, and are neurotoxic. Cell Rep 2013;5:1178-1186. Identification of hnRNP H as a protein sequestered by expanded C9orf72 repeat RNA.
25. Haeusler AR, Donnelly CJ, Periz G, et al. C9orf72 nucleotide repeat structures initiate molecular cascades of disease. Nature 2014;507:195-200. Identification of nucleolin as a binding protein of G-quadruplexes formed by expanded C9orf72 repeat RNA and evidence suggesting a role for nucleolar stress in C9FTD/ALS.
26. Xu Z, Poidevin M, Li X, et al. Expanded GGGGCC repeat RNA associated with amyotrophic lateral sclerosis and frontotemporal dementia causes neurodegeneration. Proc Natl Acad Sci U S A 2013;110:7778-7783. First description of C9orf72 repeats causing neurodegeneration in Drosophila and identification of repeat binding proteins.
27. Ash PE, Bieniek KF, Gendron TF, et al. Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. Neuron 2013;77:639-646. The first description, with reference [28], of RAN translation of the C9orf72 repeat in C9FTD/ALS.
28. Mori K, Weng SM, Arzberger T, et al. The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science 2013;339:1335-1338. The first description, with reference [27], of RAN translation of the C9orf72 repeat in C9FTD/ALS.
29. Mori K, Arzberger T, Grasser FA, et al. Bidirectional transcripts of the expanded C9orf72 hexanucleotide repeat are translated into aggregating dipeptide repeat proteins. Acta Neuropathol 2013;126:881-893. One of the first descriptions of antisense DPR protein in C9FTD/ALS patient tissue.
30. Proudfoot M, Gutowski NJ, Edbauer D, et al. Early dipeptide repeat pathology in a frontotemporal dementia kindred with C9ORF72 mutation and intellectual disability. Acta Neuropathol 2014;127:451-458. Description of two C9orf72 repeat expansion carriers with predominant and early poly-GA pathology and limited TDP-43 pathology.
31. Mackenzie IR, Arzberger T, Kremmer E, et al. Dipeptide repeat protein pathology in C9ORF72 mutation cases: clinico-pathological correlations. Acta Neuropathol 2013;126:859-879. An in-depth clinicopathological study showing that TDP-43 rather than poly-GA inclusions correlate with neurodegeneration in C9FTD/ALS.
32. Hagerman P. Fragile X-associated tremor/ataxia syndrome (FXTAS): pathology and mechanisms. Acta Neuropathol 2013;126:1-19.
33. Hagerman RJ, Leehey M, Heinrichs W, et al. Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X. Neurology 2001;57:127-130.
34. Wang T, Bray SM, Warren ST. New perspectives on the biology of fragile X syndrome. Curr Opin Genet Dev 2012;22:256-263.
35. Van Blitterswijk M, Dejesus-Hernandez M, Niemantsverdriet E, et al. Association between repeat sizes and clinical and pathological characteristics in carriers of C9ORF72 repeat expansions (Xpansize-72): a cross-sectional cohort study. Lancet Neurol 2013;12:978-988. First large study assessing repeat size and clinicopathological correlations in ALS, FTD and ALS/FTD C9orf72 repeat expansion carriers.
36. Cooper TA, Wan L, Dreyfuss G. R. N. A and disease. Cell 2009;136:777-793.
37. Zu T, Gibbens B, Doty NS, et al. Non-ATG-initiated translation directed by microsatellite expansions. Proc Natl Acad Sci U S A 2011;108:260-265.
38. Cleary JD, Ranum LP. Repeat associated non-ATG (RAN) translation: new starts in microsatellite expansion disorders. Curr Opin Genet Dev 2014;26C: 6-15.
39. Nixon RA. The role of autophagy in neurodegenerative disease. Nat Med 2013;19:983-997.
40. Wojciechowska M, Krzyzosiak WJ. Cellular toxicity of expanded RNA repeats: focus on RNA foci. Hum Mol Genet 2011;20:3811-3821.
41. Mankodi A, Takahashi MP, Jiang H, et al. Expanded CUG repeats trigger aberrant splicing of ClC-1 chloride channel premRNA and hyperexcitability of skeletal muscle in myotonic dystrophy. Mol Cell 2002;10:35-44.
42. Suzuki N, Maroof AM, Merkle FT, et al. The mouse C9ORF72 ortholog is enriched in neurons known to degenerate in ALS and FTD. Nat Neurosci 2013;16:1725-1727.
43. Meyer K, Ferraiuolo L, Miranda CJ, et al. Direct conversion of patient fibroblasts demonstrates noncell autonomous toxicity of astrocytes to motor neurons in familial and sporadic ALS. Proc Natl Acad Sci U S A 2014;111:829-832.
44. Vatovec S, Kovanda A, Rogelj B. Unconventional features of C9ORF72 expanded repeat in amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Neurobiol Aging 2014;35:e1-12; 2421.
45. Cooper-Knock J, Walsh MJ, Higginbottom A, et al. Sequestration of multiple RNA recognition motif-containing proteins by C9orf72 repeat expansions. Brain 2014;137:2040-2051. Identification of multiple RNA-binding proteins sequestered by expanded C9orf72 repeat RNA.
46. Stutz F, Bachi A, Doerks T, et al. REF, an evolutionary conserved family of hnRNP-like proteins, interacts with TAP/Mex67p and participates in mRNA nuclear export. RNA 2000;6:638-650.
47. Kanai Y, Dohmae N, Hirokawa N. Kinesin transports RNA: isolation and characterization of an RNA-transporting granule. Neuron 2004;43:513-525.
48. Johnson EM, Kinoshita Y, Weinreb DB, et al. Role of Pur alpha in targeting mRNA to sites of translation in hippocampal neuronal dendrites. J Neurosci Res 2006;83:929-943.
49. Ma AS, Moran-Jones K, Shan J, et al. Heterogeneous nuclear ribonucleoprotein A3, a novel RNA trafficking response element-binding protein. J Biol Chem 2002;277:18010-18020.
50. Chen CX, Cho DS, Wang Q, et al. A third member of the RNA-specific adenosine deaminase gene family, ADAR3, contains both single- and doublestranded RNA binding domains. RNA 2000;6:755-767.
51. Kwak S, Hideyama T, Yamashita T, et al. AMPA receptor-mediated neuronal death in sporadic ALS. Neuropathology 2010;30:182-188.
52. Fratta P, Mizielinska S, Nicoll AJ, et al. C9orf72 hexanucleotide repeat associated with amyotrophic lateral sclerosis and frontotemporal dementia forms RNA G-quadruplexes. Sci Rep 2012;2:1-6; Article 1016. doi:10.1038/srep01016. The first description of the tertiary structures formed by C9orf72 repeat RNA.
53. Reddy K, Zamiri B, Stanley SY, et al. 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 2013;288:9860-9866.
54. Ji X, Sun H, Zhou H, et al. Research progress of RNA quadruplex. Nucleic Acid Ther 2011;21:185-200.
55. Subramanian M, Rage F, Tabet R, et al. G-quadruplex RNA structure as a signal for neurite mRNA targeting. EMBO Rep 2011;12:697-704.
56. Collie GW, Parkinson GN. The application of DNA and RNA G-quadruplexes to therapeutic medicines. Chem Soc Rev 2011;40:5867-5892.
57. Banez-Coronel M, Porta S, Kagerbauer B, et al. A pathogenic mechanism in Huntington's disease involves small CAG-repeated RNAs with neurotoxic activity. PLoS Genet 2012;8:e1002481.
58. Yu Z, Teng X, Bonini NM. Triplet repeat-derived siRNAs enhance RNA-mediated toxicity in a Drosophila model for myotonic dystrophy. PLoS Genet 2011;7:e1001340.
59. Chung DW, Rudnicki DD, Yu L, et al. A natural antisense transcript at the Huntington's disease repeat locus regulates HTT expression. Hum Mol Genet 2011;20:3467-3477.
60. Mann DM, Rollinson S, Robinson A, et al. 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 2013;1:1-13; Article 68. doi:10.1186/2051-5960-1-68.
61. 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 2011;122:691-702.
62. Miller TM, Pestronk A, David W, et al. An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: a phase 1, randomised, first-in-man study. Lancet Neurol 2013;12:435-442.
63. Zamiri B, Reddy K, Macgregor RB Jr, et al. TMPyP4 porphyrin distorts RNA G-quadruplex structures of the disease-associated r (GGGGCC) n repeat of the C9orf72 gene and blocks interaction of RNA-binding proteins. J Biol Chem 2014;289:4653-4659. The study provides proof of principle for RNA G-quadruplex binding small molecules as a therapeutic strategy in C9FTD/ALS.