Towards Understanding RNA-Mediated Neurological Disorders

Ranhui Duan; Sumeet Sharma; Qiuping Xia; Kathryn Garber; Peng Jin

doi:10.1016/j.jgg.2014.08.003

Volume 41 Issue 9

Sep. 2014

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Article Navigation > Journal of Genetics and Genomics > 2014 > 41(9): 473-484

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Towards Understanding RNA-Mediated Neurological Disorders

doi: 10.1016/j.jgg.2014.08.003

a
State Key Laboratory of Medical Genetics, Central South University, Changsha 410078, China
b
Department of Human Genetics, Emory University School of Medicine, Atlanta 30322, USA

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Corresponding author: E-mail address: duanranhui@sklmg.edu.cn (Ranhui Duan); E-mail address: peng.jin@emory.edu (Peng Jin)
Received Date: 2014-05-25
Accepted Date: 2014-08-12
Rev Recd Date: 2014-08-10

Available Online: 2014-08-23

Publish Date: 2014-09-20

Abstract

Abstract

RNA-mediated mechanisms of disease pathogenesis in neurological disorders have been recognized in the context of certain repeat expansion disorders. This RNA-initiated neurodegeneration may play a more pervasive role in disease pathology beyond the classic dynamic mutation disorders. Here, we review the mechanisms of RNA toxicity and aberrant RNA processing that have been implicated in ageing-related neurological disorders. We focus on diseases with aberrant sequestration of RNA-binding proteins, bi-directional transcription, aberrant translation of repeat expansion RNA transcripts (repeat-associated non-ATG (RAN) translation), and the formation of pathological RNA:DNA secondary structure (R-loop). It is likely that repeat expansion disorders arise from common mechanisms caused by the repeat expansion mutations. However, the context of the repeat expansion determines the specific molecular consequences, leading to clinically distinct disorders.
- Neurodegeneration,
- Repeat expansion,
- RNA toxicity,
- RAN translation,
- R-loop

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References(116)

References

[1]	Aguilera, A., Garcia-Muse, T. R loops: from transcription byproducts to threats to genome stability Mol. Cell, 46 (2012),pp. 115-124
[2]	Amack, J.D., Paguio, A.P., Mahadevan, M.S. Cis and trans effects of the myotonic dystrophy (DM) mutation in a cell culture model Hum. Mol. Genet., 8 (1999),pp. 1975-1984
[3]	Amato, A.A.
[4]	Arocena, D.G., Iwahashi, C.K., Won, N. et al. 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 (2005),pp. 3661-3671
[5]	Ash, P.E., Bieniek, K.F., Gendron, T.F. et al. Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS Neuron, 77 (2013),pp. 639-646
[6]	Bartel, D.P. MicroRNAs: target recognition and regulatory functions Cell, 136 (2009),pp. 215-233
[7]	Batista, P.J., Chang, H.Y. Long noncoding RNAs: cellular address codes in development and disease Cell, 152 (2013),pp. 1298-1307
[8]	Brook, J.D., McCurrach, M.E., Harley, H.G. et al. Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat at the 3′ end of a transcript encoding a protein kinase family member Cell, 68 (1992),pp. 799-808
[9]	Charlet, B.N., Savkur, R.S., Singh, G. et al. Loss of the muscle-specific chloride channel in type 1 myotonic dystrophy due to misregulated alternative splicing Mol. Cell, 10 (2002),pp. 45-53
[10]	Colak, D., Zaninovic, N., Cohen, M.S. et al. Promoter-bound trinucleotide repeat mRNA drives epigenetic silencing in fragile X syndrome Science, 343 (2014),pp. 1002-1005
[11]	Dansithong, W., Paul, S., Comai, L. et al. MBNL1 is the primary determinant of focus formation and aberrant insulin receptor splicing in DM1 J. Biol. Chem., 280 (2005),pp. 5773-5780
[12]	David, G., Abbas, N., Stevanin, G. et al. Nat. Genet., 17 (1997),pp. 65-70
[13]	Davis, B.M., McCurrach, M.E., Taneja, K.L. et al. Expansion of a CUG trinucleotide repeat in the 3′ untranslated region of myotonic dystrophy protein kinase transcripts results in nuclear retention of transcripts Proc. Natl. Acad. Sci. USA, 94 (1997),pp. 7388-7393
[14]	Day, J.W., Schut, L.J., Moseley, M.L. et al. Spinocerebellar ataxia type 8: clinical features in a large family Neurology, 55 (2000),pp. 649-657
[15]	de Haro, M., Al-Ramahi, I., De Gouyon, B. et al. Hum. Mol. Genet., 15 (2006),pp. 2138-2145
[16]	DeJesus-Hernandez, M., Mackenzie, I.R., Boeve, B.F. et al. Neuron, 72 (2011),pp. 245-256
[17]	Donnelly, C.J., Zhang, P.W., Pham, J.T. et al. RNA toxicity from the ALS/FTD C9ORF72 expansion is mitigated by antisense intervention Neuron, 80 (2013),pp. 415-428
[18]	Encode Project Consortium An integrated encyclopedia of DNA elements in the human genome Nature, 489 (2012),pp. 57-74
[19]	Erdmann, V.A., Barciszewska, M.Z., Hochberg, A. et al. Regulatory RNAs Cell. Mol. Life Sci., 58 (2001),pp. 960-977
[20]	Faghihi, M.A., Wahlestedt, C. Regulatory roles of natural antisense transcripts Nat. Rev. Mol. Cell Biol., 10 (2009),pp. 637-643
[21]	Fardaei, M., Larkin, K., Brook, J.D. et al. Nucleic Acids Res., 29 (2001),pp. 2766-2771
[22]	Fardaei, M., Rogers, M.T., Thorpe, H.M. et al. Hum. Mol. Genet., 11 (2002),pp. 805-814
[23]	Fatica, A., Bozzoni, I. Long non-coding RNAs: new players in cell differentiation and development Nat. Rev. Genet., 15 (2014),pp. 7-21
[24]	Filipowicz, W., Bhattacharyya, S.N., Sonenberg, N. Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat. Rev. Genet., 9 (2008),pp. 102-114
[25]	Fu, Y.H., Pizzuti, A., , King, J. et al. An unstable triplet repeat in a gene related to myotonic muscular dystrophy Science, 255 (1992),pp. 1256-1258
[26]	Gendron, T.F., Belzil, V.V., Zhang, Y.J. et al. Mechanisms of toxicity in C9FTLD/ALS Acta Neuropathol., 127 (2014),pp. 359-376
[27]	Gendron, T.F., Bieniek, K.F., Zhang, Y.J. 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., 126 (2013),pp. 829-844
[28]	Giordana, M.T., Ferrero, P., Grifoni, S. et al. Dementia and cognitive impairment in amyotrophic lateral sclerosis: a review Neurol. Sci., 32 (2011),pp. 9-16
[29]	Grammatikakis, I., Goo, Y.H., Echeverria, G.V. et al. Identification of MBNL1 and MBNL3 domains required for splicing activation and repression Nucleic Acids Res., 39 (2011),pp. 2769-2780
[30]	Greco, C.M., Berman, R.F., Martin, R.M. et al. Neuropathology of fragile X-associated tremor/ataxia syndrome (FXTAS) Brain, 129 (2006),pp. 243-255
[31]	Greco, C.M., Hagerman, R.J., Tassone, F. et al. Neuronal intranuclear inclusions in a new cerebellar tremor/ataxia syndrome among fragile X carriers Brain, 125 (2002),pp. 1760-1771
[32]	Greenstein, P.E., Vonsattel, J.P., Margolis, R.L. et al. Huntington's disease like-2 neuropathology Mov. Disord., 22 (2007),pp. 1416-1423
[33]	Groh, M., Lufino, M.M., Wade-Martins, R. et al. R-loops associated with triplet repeat expansions promote gene silencing in Friedreich ataxia and fragile X syndrome PLoS Genet., 10 (2014),p. e1004318
[34]	Haeusler, A.R., Donnelly, C.J., Periz, G. et al. C9orf72 nucleotide repeat structures initiate molecular cascades of disease Nature, 507 (2014),pp. 195-200
[35]	Hagerman, P.J., Hagerman, R.J. The fragile-X premutation: a maturing perspective Am. J. Hum. Genet., 74 (2004),pp. 805-816
[36]	Hagerman, R.J., Hagerman, P.J. The fragile X premutation: into the phenotypic fold Curr. Opin. Genet. Dev., 12 (2002),pp. 278-283
[37]	Hann, S.R., King, M.W., Bentley, D.L. et al. A non-AUG translational initiation in c-myc exon 1 generates an N-terminally distinct protein whose synthesis is disrupted in Burkitt's lymphomas Cell, 52 (1988),pp. 185-195
[38]	Hastings, M.L., Ingle, H.A., Lazar, M.A. et al. J. Biol. Chem., 275 (2000),pp. 11507-11513
[39]	He, Y., Vogelstein, B., Velculescu, V.E. et al. The antisense transcriptomes of human cells Science, 322 (2008),pp. 1855-1857
[40]	Ho, T.H., Bundman, D., Armstrong, D.L. et al. Transgenic mice expressing CUG-BP1 reproduce splicing mis-regulation observed in myotonic dystrophy Hum. Mol. Genet., 14 (2005),pp. 1539-1547
[41]	Ho, T.H., Charlet, B.N., Poulos, M.G. et al. Muscleblind proteins regulate alternative splicing EMBO J., 23 (2004),pp. 3103-3112
[42]	Holmes, S.E., O'Hearn, E., Rosenblatt, A. et al. A repeat expansion in the gene encoding junctophilin-3 is associated with Huntington disease-like 2 Nat. Genet., 29 (2001),pp. 377-378
[43]	Iwahashi, C.K., Yasui, D.H., An, H.J. et al. Protein composition of the intranuclear inclusions of FXTAS Brain, 129 (2006),pp. 256-271
[44]	Jacquemont, S., Hagerman, R.J., Leehey, M. et al. Fragile X premutation tremor/ataxia syndrome: molecular, clinical, and neuroimaging correlates Am. J. Hum. Genet., 72 (2003),pp. 869-878
[45]	Jiang, H., Mankodi, A., Swanson, M.S. et al. Myotonic dystrophy type 1 is associated with nuclear foci of mutant RNA, sequestration of muscleblind proteins and deregulated alternative splicing in neurons Hum. Mol. Genet., 13 (2004),pp. 3079-3088
[46]	Jin, P., Duan, R., Qurashi, A. et al. Neuron, 55 (2007),pp. 556-564
[47]	Jin, P., Zarnescu, D.C., Zhang, F. et al. Neuron, 39 (2003),pp. 739-747
[48]	Kalsotra, A., Xiao, X., Ward, A.J. et al. A postnatal switch of CELF and MBNL proteins reprograms alternative splicing in the developing heart Proc. Natl. Acad. Sci. USA, 105 (2008),pp. 20333-20338
[49]	Kanadia, R.N., Johnstone, K.A., Mankodi, A. et al. A muscleblind knockout model for myotonic dystrophy Science, 302 (2003),pp. 1978-1980
[50]	Kanadia, R.N., Shin, J., Yuan, Y. et al. Reversal of RNA missplicing and myotonia after muscleblind overexpression in a mouse poly(CUG) model for myotonic dystrophy Proc. Natl. Acad. Sci. USA, 103 (2006),pp. 11748-11753
[51]	Kenneson, A., Zhang, F., Hagedorn, C.H. et al. Reduced FMRP and increased FMR1 transcription is proportionally associated with CGG repeat number in intermediate-length and premutation carriers Hum. Mol. Genet., 10 (2001),pp. 1449-1454
[52]	Khalil, A.M., Faghihi, M.A., Modarresi, F. et al. A novel RNA transcript with antiapoptotic function is silenced in fragile X syndrome PLoS ONE, 3 (2008),p. e1486
[53]	Knee, R., Murphy, P.R. Regulation of gene expression by natural antisense RNA transcripts Neurochem. Int., 31 (1997),pp. 379-392
[54]	Koob, M.D., Moseley, M.L., Schut, L.J. et al. An untranslated CTG expansion causes a novel form of spinocerebellar ataxia (SCA8) Nat. Genet., 21 (1999),pp. 379-384
[55]	Kozak, M. Context effects and inefficient initiation at non-AUG codons in eukaryotic cell-free translation systems Mol. Cell Biol., 9 (1989),pp. 5073-5080
[56]	Kremer, E.J., Pritchard, M., Lynch, M. et al. Mapping of DNA instability at the fragile X to a trinucleotide repeat sequence p(CCG)n Science, 252 (1991),pp. 1711-1714
[57]	Krol, J., Loedige, I., Filipowicz, W. The widespread regulation of microRNA biogenesis, function and decay Nat. Rev. Genet., 11 (2010),pp. 597-610
[58]	Kuyumcu-Martinez, N.M., Wang, G.S., Cooper, T.A. Increased steady-state levels of CUGBP1 in myotonic dystrophy 1 are due to PKC-mediated hyperphosphorylation Mol. Cell, 28 (2007),pp. 68-78
[59]	La Spada, A.R., Fu, Y.H., Sopher, B.L. et al. Polyglutamine-expanded ataxin-7 antagonizes CRX function and induces cone-rod dystrophy in a mouse model of SCA7 Neuron, 31 (2001),pp. 913-927
[60]	Ladd, P.D., Smith, L.E., Rabaia, N.A. et al. An antisense transcript spanning the CGG repeat region of FMR1 is upregulated in premutation carriers but silenced in full mutation individuals Hum. Mol. Genet., 16 (2007),pp. 3174-3187
[61]	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. USA, 110 (2013),pp. E4530-E4539
[62]	Lee, Y.B., Chen, H.J., Peres, J.N. et al. Hexanucleotide repeats in ALS/FTD form length-dependent RNA foci, sequester RNA binding proteins, and are neurotoxic Cell Rep., 5 (2013),pp. 1178-1186
[63]	Li, A.W., Murphy, P.R. Expression of alternatively spliced FGF-2 antisense RNA transcripts in the central nervous system: regulation of FGF-2 mRNA translation Mol. Cell. Endocrinol., 170 (2000),pp. 233-242
[64]	Li, Y., Jin, P. RNA-mediated neurodegeneration in fragile X-associated tremor/ataxia syndrome Brain Res., 1462 (2012),pp. 112-117
[65]	Lin, X., Miller, J.W., Mankodi, A. et al. Failure of MBNL1-dependent post-natal splicing transitions in myotonic dystrophy Hum. Mol. Genet., 15 (2006),pp. 2087-2097
[66]	Liquori, C.L., Ricker, K., Moseley, M.L. et al. Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9 Science, 293 (2001),pp. 864-867
[67]	Loomis, E.W., Sanz, L.A., Chedin, F. et al. Transcription-associated R-loop formation across the human FMR1 CGG-repeat region PLoS Genet., 10 (2014),p. e1004294
[68]	Mankodi, A., Lin, X., Blaxall, B.C. et al. Nuclear RNA foci in the heart in myotonic dystrophy Circ. Res., 97 (2005),pp. 1152-1155
[69]	Mankodi, A., Logigian, E., Callahan, L. et al. Myotonic dystrophy in transgenic mice expressing an expanded CUG repeat Science, 289 (2000),pp. 1769-1773
[70]	Mankodi, A., Takahashi, M.P., Jiang, H. et al. Expanded CUG repeats trigger aberrant splicing of ClC-1 chloride channel pre-mRNA and hyperexcitability of skeletal muscle in myotonic dystrophy Mol. Cell, 10 (2002),pp. 35-44
[71]	Mankodi, A., Urbinati, C.R., Yuan, Q.P. et al. Muscleblind localizes to nuclear foci of aberrant RNA in myotonic dystrophy types 1 and 2 Hum. Mol. Genet., 10 (2001),pp. 2165-2170
[72]	Margolis, R.L., Holmes, S.E., Rosenblatt, A. et al. Huntington's Disease-like 2 (HDL2) in North America and Japan Ann. Neurol., 56 (2004),pp. 670-674
[73]	Margolis, R.L., O'Hearn, E., Rosenblatt, A. et al. A disorder similar to Huntington's disease is associated with a novel CAG repeat expansion Ann. Neurol., 50 (2001),pp. 373-380
[74]	Marsh, J.L., Walker, H., Theisen, H. et al. Hum. Mol. Genet., 9 (2000),pp. 13-25
[75]	Miller, J.W., Urbinati, C.R., Teng-Umnuay, P. et al. Recruitment of human muscleblind proteins to (CUG)(n) expansions associated with myotonic dystrophy EMBO J., 19 (2000),pp. 4439-4448
[76]	Mizielinska, S., Lashley, T., Norona, F.E. et al. C9orf72 frontotemporal lobar degeneration is characterised by frequent neuronal sense and antisense RNA foci Acta Neuropathol., 126 (2013),pp. 845-857
[77]	Mori, K., Arzberger, T., Grasser, F.A. et al. Bidirectional transcripts of the expanded C9orf72 hexanucleotide repeat are translated into aggregating dipeptide repeat proteins Acta Neuropathol., 126 (2013),pp. 881-893
[78]	Mori, K., Lammich, S., Mackenzie, I.R. 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., 125 (2013),pp. 413-423
[79]	Mori, K., Weng, S.M., Arzberger, T. et al. The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS Science, 339 (2013),pp. 1335-1338
[80]	Moseley, M.L., Zu, T., Ikeda, Y. et al. Bidirectional expression of CUG and CAG expansion transcripts and intranuclear polyglutamine inclusions in spinocerebellar ataxia type 8 Nat. Genet., 38 (2006),pp. 758-769
[81]	Mutsuddi, M., Marshall, C.M., Benzow, K.A. et al. Curr. Biol., 14 (2004),pp. 302-308
[82]	Nelson, D.L., Orr, H.T., Warren, S.T. The unstable repeats–three evolving faces of neurological disease Neuron, 77 (2013),pp. 825-843
[83]	Oberle, I., Rousseau, F., Heitz, D. et al. Instability of a 550-base pair DNA segment and abnormal methylation in fragile X syndrome Science, 252 (1991),pp. 1097-1102
[84]	Orengo, J.P., Chambon, P., Metzger, D. et al. Expanded CTG repeats within the DMPK 3′ UTR causes severe skeletal muscle wasting in an inducible mouse model for myotonic dystrophy Proc. Natl. Acad. Sci. USA, 105 (2008),pp. 2646-2651
[85]	Peabody, D.S. Translation initiation at non-AUG triplets in mammalian cells J. Biol. Chem., 264 (1989),pp. 5031-5035
[86]	Pearson, C.E. Repeat associated non-ATG translation initiation: one DNA, two transcripts, seven reading frames, potentially nine toxic entities! PLoS Genet., 7 (2011),p. e1002018
[87]	Pieretti, M., Zhang, F.P., Fu, Y.H. et al. Cell, 66 (1991),pp. 817-822
[88]	Rademakers, R., Neumann, M., Mackenzie, I.R. Advances in understanding the molecular basis of frontotemporal dementia Nat. Rev. Neurol., 8 (2012),pp. 423-434
[89]	Renton, A.E., Majounie, E., Waite, A. et al. Neuron, 72 (2011),pp. 257-268
[90]	Robberecht, W., Philips, T. The changing scene of amyotrophic lateral sclerosis Nat. Rev. Neurosci., 14 (2013),pp. 248-264
[91]	Rudnicki, D.D., Holmes, S.E., Lin, M.W. et al. Huntington's disease–like 2 is associated with CUG repeat-containing RNA foci Ann. Neurol., 61 (2007),pp. 272-282
[92]	Rudnicki, D.D., Pletnikova, O., Vonsattel, J.P. et al. A comparison of huntington disease and huntington disease-like 2 neuropathology J. Neuropathol. Exp. Neurol., 67 (2008),pp. 366-374
[93]	Rutherford, N.J., Heckman, M.G., Dejesus-Hernandez, M. et al. Neurbiol. Aging, 33 (2012),pp. e2955-2957
[94]	Savkur, R.S., Philips, A.V., Cooper, T.A. Aberrant regulation of insulin receptor alternative splicing is associated with insulin resistance in myotonic dystrophy Nat. Genet., 29 (2001),pp. 40-47
[95]	Sellier, C., Rau, F., Liu, Y. et al. Sam68 sequestration and partial loss of function are associated with splicing alterations in FXTAS patients EMBO J., 29 (2010),pp. 1248-1261
[96]	Sen, S., Talukdar, I., Liu, Y. et al. J. Biol. Chem., 285 (2010),pp. 25426-25437
[97]	Seznec, H., Agbulut, O., Sergeant, N. et al. Mice transgenic for the human myotonic dystrophy region with expanded CTG repeats display muscular and brain abnormalities Hum. Mol. Genet., 10 (2001),pp. 2717-2726
[98]	Sofola, O.A., Jin, P., Qin, Y. et al. Neuron, 55 (2007),pp. 565-571
[99]	Stepto, A., Gallo, J.M., Shaw, C.E. et al. Modelling C9ORF72 hexanucleotide repeat expansion in amyotrophic lateral sclerosis and frontotemporal dementia Acta Neuropathol., 127 (2014),pp. 377-389
[100]	Tan, H., Poidevin, M., Li, H. et al. MicroRNA-277 modulates the neurodegeneration caused by Fragile X premutation rCGG repeats PLoS Genet., 8 (2012),p. e1002681
[101]	Taneja, K.L., McCurrach, M., Schalling, M. et al. Foci of trinucleotide repeat transcripts in nuclei of myotonic dystrophy cells and tissues J. Cell Biol., 128 (1995),pp. 995-1002
[102]	Tassone, F., Beilina, A., Carosi, C. et al. Elevated FMR1 mRNA in premutation carriers is due to increased transcription RNA, 13 (2007),pp. 555-562
[103]	Tassone, F., Hagerman, R.J., Taylor, A.K. et al. Am. J. Hum. Genet., 66 (2000),pp. 6-15
[104]	Tassone, F., Iwahashi, C., Hagerman, P.J. FMR1 RNA within the intranuclear inclusions of fragile X-associated tremor/ataxia syndrome (FXTAS) RNA Biol., 1 (2004),pp. 103-105
[105]	Timchenko, L.T., Miller, J.W., Timchenko, N.A. et al. Identification of a (CUG)n triplet repeat RNA-binding protein and its expression in myotonic dystrophy Nucleic Acids Res., 24 (1996),pp. 4407-4414
[106]	Timchenko, N.A., Cai, Z.J., Welm, A.L. et al. RNA CUG repeats sequester CUGBP1 and alter protein levels and activity of CUGBP1 J. Biol. Chem., 276 (2001),pp. 7820-7826
[107]	Todd, P.K., Oh, S.Y., Krans, A. et al. CGG repeat-associated translation mediates neurodegeneration in fragile X tremor ataxia syndrome Neuron, 78 (2013),pp. 440-455
[108]	Udd, B., Krahe, R. The myotonic dystrophies: molecular, clinical, and therapeutic challenges Lancet Neurol., 11 (2012),pp. 891-905
[109]	Verkerk, A.J., Pieretti, M., Sutcliffe, J.S. et al. Cell, 65 (1991),pp. 905-914
[110]	Wang, G.S., Kuyumcu-Martinez, M.N., Sarma, S. et al. PKC inhibition ameliorates the cardiac phenotype in a mouse model of myotonic dystrophy type 1 J. Clin. Invest., 119 (2009),pp. 3797-3806
[111]	Wilburn, B., Rudnicki, D.D., Zhao, J. et al. Neuron, 70 (2011),pp. 427-440
[112]	Willemsen, R., Hoogeveen-Westerveld, M., Reis, S. et al. Hum. Mol. Genet., 12 (2003),pp. 949-959
[113]	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. USA, 110 (2013),pp. 7778-7783
[114]	Yelin, R., Dahary, D., Sorek, R. et al. Widespread occurrence of antisense transcription in the human genome Nat. Biotechnol., 21 (2003),pp. 379-386
[115]	Zu, T., Gibbens, B., Doty, N.S. et al. Non-ATG-initiated translation directed by microsatellite expansions Proc. Natl. Acad. Sci. USA, 108 (2011),pp. 260-265
[116]	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. USA, 110 (2013),pp. E4968-E4977