Non-coding RNA in neural function, disease, and aging

Frontiers in Genetics

Volumn 6, Issue MAR, 2015, Pages

  Szafranski, Kirk ^a   Abraham, Karan J ^a   Mekhail, Karim ^a  

^a UNIVERSITY OF TORONTO   (Canada)

Author keywords

ATXN2; FUS; LncRNA; MiRNA; Neurodegeneration; R loops; SETX; TDP 43

Indexed keywords

EID: 84923536034     PISSN: None     EISSN: 16648021     Source Type: Journal    
DOI: 10.3389/fgene.2015.00087     Document Type: Review

References (140)

1. Abdelmohsen, K., Panda, A., Kang, M. J., Xu, J., Selimyan, R., Yoon, J. H.,et al. (2013). Senescence-associated lncRNAs: senescence-associated long noncoding RNAs. Aging Cell 12, 890-900. doi: 10.1111/acel.12115
2. Abe, M., and Bonini, N. M. (2013). MicroRNAs and neurodegeneration: role and impact. Trends Cell Biol. 23, 30-36. doi: 10.1016/j.tcb.2012.08.013
3. Aguilera, A., and Garcia-Muse, T. (2012). R loops: from transcription byproducts to threats to genome stability. Mol. Cell 46, 115-124. doi: 10.1016/j.molcel.2012.04.009
4. Araki, T., Sasaki, Y., and Milbrandt, J. (2004). Increased nuclear NAD biosynthesis and SIRT1 activation prevent axonal degeneration. Science 305, 1010-1013. doi: 10.1126/science.1098014
5. Bak, M., Silahtaroglu, A., Moller, M., Christensen, M., Rath, M. F., Skryabin, B.,et al. (2008). MicroRNA expression in the adult mouse central nervous system. RNA 14, 432-444. doi: 10.1261/rna.783108
6. Baloh, R. H. (2012). How do the RNA-binding proteins TDP-43 and FUS relate to amyotrophic lateral sclerosis and frontotemporal degeneration, and to each other? Curr. Opin. Neurol. 25, 701-707. doi: 10.1097/Wco.0b013e32835a269b
7. Barrachina, M., Castano, E., Dalfo, E., Maes, T., Buesa, C., and Ferrer, I. (2006). Reduced ubiquitin C-terminal hydrolase-1 expression levels in dementia with Lewy bodies. Neurobiol. Dis. 22, 265-273. doi: 10.1016/j.nbd.2005.11.005
8. Bartel, D. P. (2004). MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281-297. doi: 10.1016/S0092-8674(04)00045-5
9. Bhat, R., Crowe, E. P., Bitto, A., Moh, M., Katsetos, C. D., Garcia, F. U.,et al. (2012). Astrocyte senescence as a component of Alzheimer's disease. PLoS ONE 7:e45069. doi: 10.1371/journal.pone.0045069
10. Bilen, J., Liu, N., Burnett, B. G., Pittman, R. N., and Bonini, N. M. (2006). MicroRNA pathways modulate polyglutamine-induced neurodegeneration. Mol. Cell 24, 157-163. doi: 10.1016/j.molcel.2006.07.030
11. Bilguvar, K., Tyagi, N. K., Ozkara, C., Tuysuz, B., Bakircioglu, M., Choi, M.,et al. (2013). Recessive loss of function of the neuronal ubiquitin hydrolase UCHL1 leads to early-onset progressive neurodegeneration. Proc. Natl. Acad. Sci. U.S.A. 110, 3489-3494. doi: 10.1073/pnas.1222732110
12. Bitto, A., Sell, C., Crowe, E., Lorenzini, A., Malaguti, M., and Torres, C. (2011). Stress-induced senescence in human and rodent astrocytes. Exp. Gerontol. 46, 213-213. doi: 10.1016/j.exger.2010.11.028
13. Bremer, J., O'Connor, T., Tiberi, C., Rehrauer, H., Weis, J., and Aguzzi, A. (2010). Ablation of dicer from Murine Schwann Cells increases their proliferation while blocking myelination. PLoS ONE 5:e12450. doi: 10.1371/journal.pone.0012450
14. Buchan, J. R., Kolaitis, R. M., Taylor, J. P., and Parker, R. (2013). Eukaryotic stress granules are cleared by autophagy and Cdc48/VCP function. Cell 153, 1461-1474. doi: 10.1016/j.cell.2013.05.037
15. Carrieri, C., Cimatti, L., Biagioli, M., Beugnet, A., Zucchelli, S., Fedele, S.,et al. (2012). Long non-coding antisense RNA controls Uchl1 translation through an embedded SINEB2 repeat. Nature 491, 454-457. doi: 10.1038/Nature11508
16. Cheloufi, S., Dos Santos, C. O., Chong, M. M. W., and Hannon, G. J. (2010). A Dicer-independent miRNA biogenesis pathway that requires Ago catalysis. Nature 465, U584-U576. doi: 10.1038/Nature09092
17. Chen, D., Steele, A. D., Hutter, G., Bruno, J., Govindarajan, A., Easlon, E.,et al. (2008a). The role of calorie restriction and SIRT1 in prion-mediated neurodegeneration. Exp. Gerontol. 43, 1086-1093. doi: 10.1016/j.exger.2008.08.050
18. Chen, W. L., Lin, J. W., Huang, H. J., Wang, S. M., Su, M. T., Lee-Chen, G. J.,et al. (2008b). SCA8 mRNA expression suggests an antisense regulation of KLHL1 and correlates to SCA8 pathology. Brain Res. 1233, 176-184. doi: 10.1016/j.brainres.2008.07.096
19. Chen, J. A., and Wichterle, H. (2012). Apoptosis of limb innervating motor neurons and erosion of motor pool identity upon lineage specific dicer inactivation. Front. Neurosci. 6:69. doi: 10.3389/fnins.2012.00069
20. Choi, J., Levey, A. I., Weintraub, S. T., Rees, H. D., Gearing, M., Chin, L. S.,et al. (2004). Oxidative modifications and down-regulation of ubiquitin carboxyl-terminal hydrolase L1 associated with idiopathic Parkinson's and Alzheimer's diseases. J. Biol. Chem. 279, 13256-13264. doi: 10.1074/jbc.M314124200
21. Choi, P. S., Zakhary, L., Choi, W. Y., Caron, S., Alvarez-Saavedra, E., Miska, E. A.,et al. (2008). Members of the miRNA-200 family regulate olfactory neurogenesis. Neuron 57, 41-55. doi: 10.1016/j.neuron.2007.11.018
22. Colak, D., Zaninovic, N., Cohen, M. S., Rosenwaks, Z., Yang, W. Y., Gerhardt, J.,et al. (2014). Promoter-bound trinucleotide repeat mRNA drives epigenetic silencing in fragile X syndrome. Science 343, 1002-1005. doi: 10.1126/science.1245831
23. Colombrita, C., Zennaro, E., Fallini, C., Weber, M., Sommacal, A., Buratti, E.,et al. (2009). TDP-43 is recruited to stress granules in conditions of oxidative insult. J. Neurochem. 111, 1051-1061. doi: 10.1111/j.1471-4159.2009.06383.x
24. Damiani, D., Alexander, J. J., O'Rourke, J. R., Mcmanus, M., Jadhav, A. P., Cepko, C. L.,et al. (2008). Dicer inactivation leads to progressive functional and structural degeneration of the mouse retina. J. Neurosci. 28, 4878-4887. doi: 10.1523/JNEUROSCI.0828-08.2008
25. Damrath, E., Heck, M. V., Gispert, S., Azizov, M., Nowock, J., Seifried, C.,et al. (2012). ATXN2-CAG42 sequesters PABPC1 into insolubility and induces FBXW8 in cerebellum of old Ataxic Knock-in mice. PLoS Genet. 8:e1002920. doi: 10.1371/journal.pgen.1002920
26. Davis, T. H., Cuellar, T. L., Koch, S. M., Barker, A. J., Harfe, B. D., Mcmanus, M. T.,et al. (2008). Conditional loss of dicer disrupts cellular and tissue morphogenesis in the cortex and hippocampus. J. Neurosci. 28, 4322-4330. doi: 10.1523/JNEUROSCI.4815-07.2008
27. 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
28. Di Sante, G., Wang, L., Wang, C., Jiao, X., Casimiro, M. C., Chen, K.,et al. (2015). Sirt1-deficient mice have hypogonadotropic hypogonadism due to defective GnRH neuronal migration. Mol. Endocrinol. 29, 200-212. doi: 10.1210/me.2014-1228
29. Djebali, S., Davis, C. A., Merkel, A., Dobin, A., Lassmann, T., Mortazavi, A.,et al. (2012). Landscape of transcription in human cells. Nature 489, 101-108. doi: 10.1038/nature11233
30. Doi, H., Koyano, S., Suzuki, Y., Nukina, N., and Kuroiwa, Y. (2010). The RNA-binding protein FUS/TLS is a common aggregate-interacting protein in polyglutamine diseases. Neurosci. Res. 66, 131-133. doi: 10.1016/j.neures.2009.10.004
31. Doi, H., Okamura, K., Bauer, P. O., Furukawa, Y., Shimizu, H., Kurosawa, M.,et al. (2008). RNA-binding protein TLS is a major nuclear aggregate-interacting protein in huntingtin exon 1 with expanded polyglutamine-expressing cells. J. Biol. Chem. 283, 6489-6500. doi: 10.1074/jbc.M705306200
32. 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
33. Eacker, S. M., Dawson, T. M., and Dawson, V. L. (2009). Understanding microRNAs in neurodegeneration. Nat. Rev. Neurosci. 10, 837-841. doi: 10.1038/nrn2726
34. Elden, A. C., Kim, H. J., Hart, M. P., Chen-Plotkin, A. S., Johnson, B. S., Fang, X.,et al. (2010). Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature 466, 1069-1075. doi: 10.1038/nature09320
35. Esteller, M. (2011). Non-coding RNAs in human disease. Nat. Rev. Genet. 12, 861-874. doi: 10.1038/Nrg3074
36. Faghihi, M. A., Modarresi, F., Khalil, A. M., Wood, D. E., Sahagan, B. G., Morgan, T. E.,et al. (2008). Expression of a noncoding RNA is elevated in Alzheimer's disease and drives rapid feed-forward regulation of beta-secretase. Nat. Med. 14, 723-730. doi: 10.1038/Nm1784
37. Fan, Z., Chen, X., and Chen, R. (2014). Transcriptome-wide analysis of TDP-43 binding small RNAs identifies miR-NID1 (miR-8485), a novel miRNA that represses NRXN1 expression. Genomics 103, 76-82. doi: 10.1016/j.ygeno.2013.06.006
38. Feldman, E. L., Boulis, N. M., Hur, J., Johe, K., Rutkove, S. B., Federici, T.,et al. (2014). Intraspinal neural stem cell transplantation in amyotrophic lateral sclerosis: phase 1 trial outcomes. Ann. Neurol. 75, 363-373. doi: 10.1002/ana.24113
39. Freischmidt, A., Muller, K., Ludolph, A. C., and Weishaupt, J. H. (2013). Systemic dysregulation of TDP-43 binding microRNAs in amyotrophic lateral sclerosis. Acta Neuropathol. Commun. 1:42. doi: 10.1186/2051-5960-1-42
40. Gaczynska, M., Osmulski, P. A., and Ward, W. F. (2001). Caretaker or undertaker? The role of the proteasome in aging. Mech. Ageing Dev. 122, 235-254. doi: 10.1016/S0047-6374(00)00246-3
41. Geisler, S., and Coller, J. (2013). RNA in unexpected places: long non-coding RNA functions in diverse cellular contexts. Nat. Rev. Mol. Cell Biol. 14, 699-712. doi: 10.1038/nrm3679
42. Giraldez, A. J., Cinalli, R. M., Glasner, M. E., Enright, A. J., Thomson, J. M., Baskerville, S.,et al. (2005). MicroRNAs regulate brain morphogenesis in zebrafish. Science 308, 833-838. doi: 10.1126/science.1109020
43. Goodenbour, J. M., and Pan, T. (2006). Diversity of tRNA genes in eukaryotes. Nucleic Acids Res. 34, 6137-6146. doi: 10.1093/Nar/Gkl725
44. Graff, J., Kahn, M., Samiei, A., Gao, J., Ota, K. T., Rei, D.,et al. (2013). A Dietary regimen of Caloric Restriction or pharmacological activation of SIRT1 to delay the onset of neurodegeneration. J. Neurosci. 33, 8951-8960. doi: 10.1523/Jneurosci.5657-12.2013
45. Groh, M., Lufino, M. M., Wade-Martins, R., and Gromak, N. (2014). R-loops associated with triplet repeat expansions promote gene silencing in Friedreich ataxia and fragile X syndrome. PLoS Genet 10:e1004318. doi: 10.1371/journal.pgen.1004318
46. Ha, M., and Kim, V. N. (2014). Regulation of microRNA biogenesis. Nat. Rev. Mol. Cell Biol. 15, 509-524. doi: 10.1038/Nrm3838
47. Haeusler, A. R., Donnelly, C. J., Periz, G., Simko, E. A. J., 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
48. Halliday, M., and Mallucci, G. R. (2014). Targeting the unfolded protein response in neurodegeneration: a new approach to therapy. Neuropharmacology 76(Pt A), 169-174. doi: 10.1016/j.neuropharm.2013.08.034
49. Haramati, S., Chapnik, E., Sztainberg, Y., Eilam, R., Zwang, R., Gershoni, N.,et al. (2010). miRNA malfunction causes spinal motor neuron disease. Proc. Natl. Acad. Sci. U.S.A. 107, 13111-13116. doi: 10.1073/pnas.1006151107
50. Hardiman, O., van den Berg, L. H., and Kiernan, M. C. (2011). Clinical diagnosis and management of amyotrophic lateral sclerosis. Nat. Rev. Neurol. 7, 639-649. doi: 10.1038/nrneurol.2011.153
51. He, L., and Hannon, G. J. (2004). MicroRNAs: small RNAs with a big role in gene regulation. Nat. Rev. Genet. 5, 522-531. doi: 10.1038/nrg1379
52. Hebert, S. S., Horre, K., Nicolai, L., Papadopoulou, A. S., Mandemakers, W., Silahtaroglu, A. N.,et al. (2008). Loss of microRNA cluster miR-29a/b-1 in sporadic Alzheimer's disease correlates with increased BACE1/beta-secretase expression. Proc. Natl. Acad. Sci. U.S.A. 105, 6415-6420. doi: 10.1073/pnas.0710263105
53. Huang, P. S., Son, J. H., Abbott, L. C., and Winzer-Serhan, U. H. (2011). Regulated expression of neuronal sirt1 and related genes by aging and neuronal beta 2-containing nicotinic cholinergic receptors. Neuroscience 196, 189-202. doi: 10.1016/j.neuroscience.2011.09.007
54. Huang, T., Liu, Y., Huang, M., Zhao, X., and Cheng, L. (2010). Wnt1-cre-mediated conditional loss of dicer results in malformation of the midbrain and cerebellum and failure of neural crest and dopaminergic differentiation in mice. J. Mol. Cell Biol. 2, 152-163. doi: 10.1093/jmcb/mjq008
55. Inukai, S., De Lencastre, A., Turner, M., and Slack, F. (2012). Novel microRNAs differentially expressed during aging in the mouse brain. PLoS ONE 7:e40028. doi: 10.1371/journal.pone.0040028
56. Ip, J. Y., and Nakagawa, S. (2012). Long non-coding RNAs in nuclear bodies. Dev. Growth Differ. 54, 44-54. doi: 10.1111/j.1440-169X.2011.01303.x
57. Ishimura, R., Nagy, G., Dotu, I., Zhou, H. H., Yang, X. L., Schimmel, P.,et al. (2014). Ribosome stalling induced by mutation of a CNS-specific tRNA causes neurodegeneration. Science 345, 455-459. doi: 10.1126/science.1249749
58. Janssen, H. L., Reesink, H. W., Lawitz, E. J., Zeuzem, S., Rodriguez-Torres, M., Patel, K.,et al. (2013). Treatment of HCV infection by targeting microRNA. N. Engl. J. Med. 368, 1685-1694. doi: 10.1056/NEJMoa1209026
59. Jiang, M. L., Wang, J. W., Fu, J. R., Du, L., Jeong, H., West, T.,et al. (2012). Neuroprotective role of Sirt1 in mammalian models of Huntington's disease through activation of multiple Sirt1 targets. Nat. Med. 18, 153-158. doi: 10.1038/Nm.2558
60. Johnson, R. (2012). Long non-coding RNAs in Huntington's disease neurodegeneration. Neurobiol. Dis. 46, 245-254. doi: 10.1016/j.nbd.2011.12.006
61. Jovicic, A., Roshan, R., Moisoi, N., Pradervand, S., Moser, R., Pillai, B.,et al. (2013). Comprehensive expression analyses of neural cell-type-specific miRNAs identify new determinants of the specification and maintenance of neuronal phenotypes. J. Neurosci. 33, 5127-5137. doi: 10.1523/JNEUROSCI.0600-12.2013
62. Kabashi, E., Valdmanis, P. N., Dion, P., Spiegelman, D., Mcconkey, B. J., Vande Velde, C.,et al. (2008). TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat. Genet. 40, 572-574. doi: 10.1038/ng.132
63. Karres, J. S., Hilgers, V., Carrera, I., Treisman, J., and Cohen, S. M. (2007). The conserved microRNA miR-8 tunes atrophin levels to prevent neurodegeneration in Drosophila. Cell 131, 136-145. doi: 10.1016/j.cell.2007.09.020
64. Kawahara, Y., and Mieda-Sato, A. (2012). TDP-43 promotes microRNA biogenesis as a component of the Drosha and Dicer complexes. Proc. Natl. Acad. Sci. U.S.A. 109, 3347-3352. doi: 10.1073/pnas.1112427109
65. Khanna, S., Rink, C., Ghoorkhanian, R., Gnyawali, S., Heigel, M., Wijesinghe, D. S.,et al. (2013). Loss of miR-29b following acute ischemic stroke contributes to neural cell death and infarct size. J. Cereb. Blood Flow Metab. 33, 1197-1206. doi: 10.1038/jcbfm.2013.68
66. Kim, D., Nguyen, M. D., Dobbin, M. M., Fischer, A., Sananbenesi, F., Rodgers, J. T.,et al. (2007a). SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis. EMBO J. 26, 3169-3179. doi: 10.1038/sj.emboj.7601758
67. Kim, J., Inoue, K., Ishii, J., Vanti, W. B., Voronov, S. V., Murchison, E.,et al. (2007b). A MicroRNA feedback circuit in midbrain dopamine neurons. Science 317, 1220-1224. doi: 10.1126/science.1140481
68. King, I. N., Yartseva, V., Salas, D., Kumar, A., Heidersbach, A., Ando, D. M.,et al. (2014). The RNA-binding protein TDP-43 selectively disrupts microRNA-1/206 incorporation into the RNA-induced silencing complex. J. Biol. Chem. 289, 14263-14271. doi: 10.1074/jbc.M114.561902
69. Kole, A. J., Swahari, V., Hammond, S. M., and Deshmukh, M. (2011). miR-29b is activated during neuronal maturation and targets BH3-only genes to restrict apoptosis. Genes Dev. 25, 125-130. doi: 10.1101/gad.1975411
70. Koob, M. D., Moseley, M. L., Schut, L. J., Benzow, K. A., Bird, T. D., Day, J. W.,et al. (1999). An untranslated CTG expansion causes a novel form of spinocerebellar ataxia (SCA8). Nat. Genet. 21, 379-384. doi: 10.1038/7710
71. Kordasiewicz, H. B., Stanek, L. M., Wancewicz, E. V., Mazur, C., Mcalonis, M. M., Pytel, K. A.,et al. (2012). Sustained therapeutic reversal of Huntington's disease by transient repression of huntingtin synthesis. Neuron 74, 1031-1044. doi: 10.1016/j.neuron.2012.05.009
72. Kwiatkowski, T. J. Jr., Bosco, D. A., Leclerc, A. L., Tamrazian, E., Vanderburg, C. R., Russ, C.,et al. (2009). Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science 323, 1205-1208. doi: 10.1126/science.1166066
73. Lagier-Tourenne, C., and Cleveland, D. W. (2009). Rethinking ALS: the FUS about TDP-43. Cell 136, 1001-1004. doi: 10.1016/j.cell.2009.03.006
74. Lee, J. W., Beebe, K., Nangle, L. A., Jang, J. S., Longo-Guess, C. M., Cook, S. A.,et al. (2006). Editing-defective tRNA synthetase causes protein misfolding and neurodegeneration. Nature 443, 50-55. doi: 10.1038/Nature05096
75. Lee, S. T., Chu, K., Im, W. S., Yoon, H. J., Im, J. Y., Park, J. E.,et al. (2011). Altered microRNA regulation in Huntington's disease models. Exp. Neurol. 227, 172-179. doi: 10.1016/j.expneurol.2010.10.012
76. Lee, Y., Jeon, K., Lee, J. T., Kim, S., and Kim, V. N. (2002). MicroRNA maturation: stepwise processing and subcellular localization. EMBO J. 21, 4663-4670. doi: 10.1093/emboj/cdf476
77. Li, L. B., Yu, Z. M., Teng, X. Y., and Bonini, N. M. (2008). RNA toxicity is a component of ataxin-3 degeneration in Drosophila. Nature 453, U1107-U1109. doi: 10.1038/Nature06909
78. Li, N., Bates, D. J., An, J., Terry, D. A., and Wang, E. (2011a). Up-regulation of key microRNAs, and inverse down-regulation of their predicted oxidative phosphorylation target genes, during aging in mouse brain. Neurobiol. Aging 32, 944-955. doi: 10.1016/j.neurobiolaging.2009.04.020
79. Li, X., Khanna, A., Li, N., and Wang, E. (2011b). Circulatory miR34a as an RNAbased, noninvasive biomarker for brain aging. Aging (Albany, NY) 3, 985-1002.
80. Liu, G. H., Qu, J., Suzuki, K., Nivet, E., Li, M., Montserrat, N.,et al. (2012). Progressive degeneration of human neural stem cells caused by pathogenic LRRK2. Nature 491, 603-607. doi: 10.1038/nature11557 doi: 10.1038/nature11557
81. Liu, T., Huang, Y., Chen, J., Chi, H., Yu, Z., Wang, J.,et al. (2014). Attenuated ability of BACE1 to cleave the amyloid precursor protein via silencing long noncoding RNA BACE1AS expression. Mol. Med. Rep. 10, 1275-1281. doi: 10.3892/mmr.2014.2351
82. Macias, S., Plass, M., Stajuda, A., Michlewski, G., Eyras, E., and Caceres, J. F. (2012). DGCR8 HITS-CLIP reveals novel functions for the Microprocessor. Nat. Struct. Mol. Biol. 19, 760-766. doi: 10.1038/Nsmb.2344
83. Mackenzie, I. R. A., Rademakers, R., and Neumann, M. (2010). TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia. Lancet Neurol. 9, 995-1007. doi: 10.1016/S1474-4422(10)70195-2
84. 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
85. Mattson, M. P. (2004). Pathways towards and away from Alzheimer's disease. Nature 430, 631-639. doi: 10.1038/Nature02621
86. McCann, C., Holohan, E. E., Das, S., Dervan, A., Larkin, A., Lee, J. A.,et al. (2011). The Ataxin-2 protein is required for microRNA function and synapse-specific long-term olfactory habituation. Proc. Natl. Acad. Sci. U.S.A. 108, E655-E662. doi: 10.1073/pnas.1107198108
87. Michelhaugh, S. K., Lipovich, L., Blythe, J., Jia, H., Kapatos, G., and Bannon, M. J. (2011). Mining Affymetrix microarray data for long non-coding RNAs: altered expression in the nucleus accumbens of heroin abusers. J. Neurochem. 116, 459-466. doi: 10.1111/j.1471-4159.2010.07126.x
88. Ming, G. L., and Song, H. (2011). Adult neurogenesis in the mammalian brain: significant answers and significant questions. Neuron 70, 687-702. doi: 10.1016/j.neuron.2011.05.001
89. Mizielinska, S., Gronke, 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
90. Modarresi, F., Faghihi, M. A., Patel, N. S., Sahagan, B. G., Wahlestedt, C., and Lopez-Toledano, M. A. (2011). Knockdown of BACE1-AS nonprotein-coding transcript modulates beta-amyloid-related hippocampal neurogenesis. Int. J. Alzheimers Dis. 2011, 929042. doi: 10.4061/2011/929042
91. Morlando, M., Modigliani, S. D., Torrelli, G., Rosa, A., Di Carlo, V., Caffarelli, E.,et al. (2012). FUS stimulates microRNA biogenesis by facilitating co-transcriptional Drosha recruitment. EMBO J. 31, 4502-4510. doi: 10.1038/emboj.2012.319
92. Mutsuddi, M., and Rebay, I. (2005). Molecular genetics of spinocerebellar ataxia type 8 (SCA8). RNA Biol. 2, 49-52. doi: 10.4161/rna.2.2.1682
93. Nakagawa, S., and Hirose, T. (2012). Paraspeckle nuclear bodies-useful uselessness? Cell. Mol. Life Sci. 69, 3027-3036. doi: 10.1007/s00018-012-0973-x
94. Nakama, M., Kawakami, K., Kajitani, T., Urano, T., and Murakami, Y. (2012). DNA-RNA hybrid formation mediates RNAi-directed heterochromatin formation. Genes Cells 17, 218-233. doi: 10.1111/j.1365-2443.2012.01583.x
95. Nalavade, R., Griesche, N., Ryan, D. P., Hildebrand, S., and Krauss, S. (2013). Mechanisms of RNA-induced toxicity in CAG repeat disorders. Cell Death Dis. 4:e752. doi: 10.1038/cddis.2013.276
96. Nemes, J. P., Benzow, K. A., Moseley, M. L., Ranum, L. P. W., and Koob, M. D. (2000). The SCA8 transcript is an antisense RNA to a brain-specific transcript encoding a novel actin-binding protein (KLHL1) (vol 9, pg 1543, 2000). Hum. Mol. Genet. 9, 2777-2777. doi: 10.1093/hmg/9.10.1543
97. 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
98. Nishimoto, Y., Nakagawa, S., Hirose, T., Okano, H. J., Takao, M., Shibata, S.,et al. (2013). The long non-coding RNA nuclear-enriched abundant transcript 1_2 induces paraspeckle formation in the motor neuron during the early phase of amyotrophic lateral sclerosis. Mol. Brain 6:31. doi: 10.1186/1756-6606-6-31
99. O'Brien, R. J., and Wong, P. C. (2011). Amyloid precursor protein processing and Alzheimer's disease. Annu. Rev. Neurosci. 34, 185-204. doi: 10.1146/annurev-neuro-061010-113613
100. Palazzo, A. F., and Gregory, T. R. (2014). The case for junk DNA. PLoS Genet. 10:e1004351. doi: 10.1371/journal.pgen.1004351
101. Pearson, C. E. (2011). Repeat associated non-ATG translation initiation: one DNA, two transcripts, seven reading frames, potentially nine toxic entities! PLoS Genet. 7:e1002018. doi: 10.1371/journal.pgen.1002018
102. Persengiev, S., Kondova, I., Otting, N., Koeppen, A. H., and Bontrop, R. E. (2011). Genome-wide analysis of miRNA expression reveals a potential role for miR-144 in brain aging and spinocerebellar ataxia pathogenesis. Neurobiol. Aging 32, 2316 e2317-2316 e2327. doi: 10.1016/j.neurobiolaging.2010.03.014
103. Prasanth, K. V., Prasanth, S. G., Xuan, Z., Hearn, S., Freier, S. M., Bennett, C. F.,et al. (2005). Regulating gene expression through RNA nuclear retention. Cell 123, 249-263. doi: 10.1016/j.cell.2005.08.033
104. Pulst, S. M., Nechiporuk, A., Nechiporuk, T., Gispert, S., Chen, X. N., Lopes-Cendes, I.,et al. (1996). Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2. Nat. Genet. 14, 269-276. doi: 10.1038/ng1196-269
105. Robberecht, W., and Philips, T. (2013). The changing scene of amyotrophic lateral sclerosis. Nat. Rev. Neurosci. 14, 248-264. doi: 10.1038/nrn3430
106. Roshan, R., Shridhar, S., Sarangdhar, M. A., Banik, A., Chawla, M., Garg, M.,et al. (2014). Brain-specific knockdown of miR-29 results in neuronal cell death and ataxia in mice. RNA 20, 1287-1297. doi: 10.1261/rna.044008.113
107. Ross, C. A., Becher, M. W., Colomer, V., Engelender, S., Wood, J. D., and Sharp, A. H. (1997). Huntington's disease and dentatorubral-pallidoluysian atrophy: proteins, pathogenesis and pathology. Brain Pathol. 7, 1003-1016. doi: 10.1111/j.1750-3639.1997.tb00898.x
108. Ross, O. A., Rutherford, N. J., Baker, M., Soto-Ortolaza, A. I., Carrasquillo, M. M., Dejesus-Hernandez, M.,et al. (2011). Ataxin-2 repeat-length variation and neurodegeneration. Hum. Mol. Genet. 20, 3207-3212. doi: 10.1093/Hmg/Ddr227
109. Sahoo, T., Del Gaudio, D., German, J. R., Shinawi, M., Peters, S. U., Person, R. E.,et al. (2008). Prader-Willi phenotype caused by paternal deficiency for the HBII-85 C/D box small nucleolar RNA cluster. Nat. Genet. 40, 719-721. doi: 10.1038/ng.158
110. Salvi, J. S., Chan, J. N. Y., Szafranski, K., Liu, T. T., Wu, J. D., Olsen, J. B.,et al. (2014). Roles for Pbp1 and Caloric Restriction in genome and lifespan maintenance via suppression of RNA-DNA Hybrids. Dev. Cell 30, 177-191. doi: 10.1016/j.devcel.2014.05.013
111. Salvi, J. S., and Mekhail, K. (2015). R-loops highlight the nucleus in ALS. Nucleus doi: 10.1080/19491034.2015.1004952 [Epub ahead of print].
112. Schaefer, A., O'carroll, D., Tan, C. L., Hillman, D., Sugimori, M., Llinas, R.,et al. (2007). Cerebellar neurodegeneration in the absence of microRNAs. J. Exp. Med. 204, 1553-1558. doi: 10.1084/jem.20070823
113. Schaffer, A. E., Eggens, V. R., Caglayan, A. O., Reuter, M. S., Scott, E., Coufal, N. G.,et al. (2014). CLP1 founder mutation links tRNA splicing and maturation to cerebellar development and neurodegeneration. Cell 157, 651-663. doi: 10.1016/j.cell.2014.03.049
114. Schwer, B., Schumacher, B., Lombard, D. B., Xiao, C. Y., Kurtev, M. V., Gao, J.,et al. (2010). Neural sirtuin 6 (Sirt6) ablation attenuates somatic growth and causes obesity. Proc. Natl. Acad. Sci. U.S.A. 107, 21790-21794. doi: 10.1073/pnas.1016306107
115. Seng, S., Avraham, H. K., Jiang, S., Venkatesh, S., and Avraham, S. (2006). KLHL1/MRP2 mediates neurite outgrowth in a glycogen synthase kinase 3beta-dependent manner. Mol. Cell. Biol. 26, 8371-8384. doi: 10.1128/MCB.02167-5
116. Sheinerman, K. S., Tsivinsky, V. G., Abdullah, L., Crawford, F., and Umansky, S. R. (2013). Plasma microRNA biomarkers for detection of mild cognitive impairment: biomarker validation study. Aging (Albany, NY) 5, 925-938.
117. Shelkovnikova, T. A., Robinson, H. K., Troakes, C., Ninkina, N., and Buchman, V. L. (2014). Compromised paraspeckle formation as a pathogenic factor in FUSopathies. Hum. Mol. Genet. 23, 2298-2312. doi: 10.1093/hmg/ddt622
118. Shin, D., Shin, J. Y., Mcmanus, M. T., Ptacek, L. J., and Fu, Y. H. (2009). Dicer ablation in oligodendrocytes provokes neuronal impairment in mice. Ann. Neurol. 66, 843-857. doi: 10.1002/ana.21927
119. Shindler, K. S., Ventura, E., Dutt, M., Elliott, P., Fitzgerald, D. C., and Rostami, A. (2010). Oral resveratrol reduces neuronal damage in a model of multiple sclerosis. J. Neuroophthalmol. 30, 328-339. doi: 10.1097/Wno.0b013e3181f7f833
120. Skourti-Stathaki, K., and Proudfoot, N. J. (2014). A double-edged sword: r loops as threats to genome integrity and powerful regulators of gene expression. Genes Dev. 28, 1384-1396. doi: 10.1101/gad.242990.114
121. Skourti-Stathaki, K., Proudfoot, N. J., and Gromak, N. (2011). Human senataxin resolves RNA/DNA hybrids formed at transcriptional pause sites to promote Xrn2-dependent termination. Mol. Cell 42, 794-805. doi: 10.1016/j.molcel.2011.04.026
122. Sun, Q. W., Csorba, T., Skourti-Stathaki, K., Proudfoot, N. J., and Dean, C. (2013). R-Loop stabilization represses antisense transcription at the Arabidopsis FLC locus. Science 340, 619-621. doi: 10.1126/science.1234848
123. Szafranski, K., and Mekhail, K. (2014). The fine line between lifespan extension and shortening in response to caloric restriction. Nucleus 5, 56-65. doi: 10.4161/nucl.27929
124. Takahama, K., Takada, A., Tada, S., Shimizu, M., Sayama, K., Kurokawa, R.,et al. (2013). Regulation of telomere length by G-quadruplex telomere DNA- and TERRA-binding protein TLS/FUS. Chem. Biol. 20, 341-350. doi: 10.1016/j.chembiol.2013.02.013
125. Tao, J., Wu, H., Lin, Q., Wei, W., Lu, X. H., Cantle, J. P.,et al. (2011). Deletion of astroglial dicer causes non-cell-autonomous neuronal dysfunction and degeneration. J. Neurosci. 31, 8306-8319. doi: 10.1523/JNEUROSCI.0567-11.2011
126. Todd, P. K., Oh, S. Y., Krans, A., He, F., Sellier, C., Frazer, M.,et al. (2013). CGG repeat-associated translation mediates neurodegeneration in fragile X tremor ataxia syndrome. Neuron 78, 440-455. doi: 10.1016/j.neuron.2013.03.026
127. Tsoi, H., and Chan, H. Y. (2013). Expression of expanded CAG transcripts triggers nucleolar stress in Huntington's disease. Cerebellum 12, 310-312. doi: 10.1007/s12311-012-0447-6
128. Tsoi, H., Lau, T. C., Tsang, S. Y., Lau, K. F., and Chan, H. Y. (2012). CAG expansion induces nucleolar stress in polyglutamine diseases. Proc. Natl. Acad. Sci. U.S.A. 109, 13428-13433. doi: 10.1073/pnas.1204089109
129. Vance, C., Rogelj, B., Hortobagyi, T., De Vos, K. J., Nishimura, A. L., Sreedharan, J.,et al. (2009). Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science 323, 1208-1211. doi: 10.1126/science.1165942
130. Wahba, L., Amon, J. D., Koshland, D., and Vuica-Ross, M. (2011). RNase H and multiple RNA biogenesis factors cooperate to prevent RNA:DNA hybrids from generating genome instability. Mol. Cell. 44, 978-988. doi: 10.1016/j.molcel.2011.10.017
131. Wang, L. C., Chen, K. Y., Pan, H., Wu, C. C., Chen, P. H., Liao, Y. T.,et al. (2011a). Muscleblind participates in RNA toxicity of expanded CAG and CUG repeats in Caenorhabditis elegans. Cell Mol. Life Sci. 68, 1255-1267. doi: 10.1007/s00018-010-0522-4
132. Wang, W. X., Huang, Q., Hu, Y., Stromberg, A. J., and Nelson, P. T. (2011b). Patterns of microRNA expression in normal and early Alzheimer's disease human temporal cortex: white matter versus gray matter. Acta Neuropathol. 121, 193-205. doi: 10.1007/s00401-010-0756-0
133. Wang, X., Liu, P., Zhu, H., Xu, Y., Ma, C., Dai, X.,et al. (2009). miR-34a, a microRNA up-regulated in a double transgenic mouse model of Alzheimer's disease, inhibits bcl2 translation. Brain Res. Bull. 80, 268-273. doi: 10.1016/j.brainresbull.2009.08.006
134. Wirdefeldt, K., Adami, H. O., Cole, P., Trichopoulos, D., and Mandel, J. (2011). Epidemiology and etiology of Parkinson's disease: a review of the evidence. Eur. J. Epidemiol. 26(Suppl. 1), S1-S58. doi: 10.1007/s10654-011-9581-6
135. Wood, S. H., Craig, T., Li, Y., Merry, B., and De Magalhaes, J. P. (2013). Whole transcriptome sequencing of the aging rat brain reveals dynamic RNA changes in the dark matter of the genome. Age 35, 763-776. doi: 10.1007/s11357-012-9410-1
136. Wu, P., Zuo, X. L., Deng, H. L., Liu, X. X., Liu, L., and Ji, A. M. (2013). Roles of long noncoding RNAs in brain development, functional diversification and neurodegenerative diseases. Brain Res. Bull. 97, 69-80. doi: 10.1016/j.brainresbull.2013.06.001
137. Xu, Z. H., Poidevin, M., Li, X. K., Li, Y. J., Shu, L. Q., Nelson, D. L.,et al. (2013). Expanded GGGGCC repeat RNA associated with amyotrophic lateral sclerosis and frontotemporal dementia causes neurodegeneration. Proc. Natl. Acad. Sci. U.S.A. 110, 7778-7783. doi: 10.1073/pnas.1219643110
138. Yeo, A. J., Becherel, O. J., Luff, J. E., Cullen, J. K., Wongsurawat, T., Jenjaroenpoon, P.,et al. (2014). R-loops in proliferating cells but not in the brain: implications for AOA2 and other autosomal recessive ataxias. PLoS ONE 9:e90219. doi: 10.1371/journal.pone.0090219
139. Yuce, O., and West, S. C. (2013). Senataxin, defective in the neurodegenerative disorder Ataxia with oculomotor apraxia 2, lies at the interface of transcription and the DNA damage response. Mol. Cell. Biol. 33, 406-417. doi: 10.1128/Mcb.01195-2
140. 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