RNA Degradation in Neurodegenerative Disease

  • Kaitlin Weskamp
  • Sami J. BarmadaEmail author
Part of the Advances in Neurobiology book series (NEUROBIOL, volume 20)


Ribonucleic acid (RNA) homeostasis is dynamically modulated in response to changing physiological conditions. Tight regulation of RNA abundance through both transcription and degradation determines the amount, timing, and location of protein translation. This balance is of particular importance in neurons, which are among the most metabolically active and morphologically complex cells in the body. As a result, any disruptions in RNA degradation can have dramatic consequences for neuronal health. In this chapter, we will first discuss mechanisms of RNA stabilization and decay. We will then explore how the disruption of these pathways can lead to neurodegenerative disease.


RNA Decay Alternative splicing Transport Stress granule Exosome Disease Neurodegeneration 


  1. 1.
    Yang L, Duff MO, Graveley BR, Carmichael GG, Chen L-L. Genomewide characterization of non-polyadenylated RNAs. Genome Biol. 2011;12:R16. Scholar
  2. 2.
    Guhaniyogi J, Brewer G. Regulation of mRNA stability in mammalian cells. Gene. 2001;265:11–23. Available: Scholar
  3. 3.
    Gerstel B, Tuite MF, McCarthy JEG. The effects of 5′-capping, 3′-polyadenylation and leader composition upon the translation and stability of mRNA in a cell-free extract derived from the yeast Saccharomyces cerevisiae. Mol Microbiol Wiley Online Library. 1992;6:2339–48. Available: Scholar
  4. 4.
    Huang Y, Carmichael GG. Role of polyadenylation in nucleocytoplasmic transport of mRNA. Mol Cell Biol. 1996;16:1534–42. Available: Scholar
  5. 5.
    Bienroth S, Keller W, Wahle E. Assembly of a processive messenger RNA polyadenylation complex. EMBO J. 1993;12:585–94. Available: Scholar
  6. 6.
    Wahle E. Poly(A) tail length control is caused by termination of processive synthesis. J Biol Chem. 1995;270:2800–8. Available: Scholar
  7. 7.
    Coller JM, Gray NK, Wickens MP. mRNA stabilization by poly(A) binding protein is independent of poly(A) and requires translation. Genes Dev. 1998;12:3226–35. Available: Scholar
  8. 8.
    Tian B, Hu J, Zhang H, Lutz CS. A large-scale analysis of mRNA polyadenylation of human and mouse genes. Nucleic Acids Res. 2005;33:201–12. Scholar
  9. 9.
    Shell SA, Hesse C, Morris SM Jr, Milcarek C. Elevated levels of the 64-kDa cleavage stimulatory factor (CstF-64) in lipopolysaccharide-stimulated macrophages influence gene expression and induce alternative poly(A) site selection. J Biol Chem. 2005;280:39950–61. Scholar
  10. 10.
    Wood AJ, Schulz R, Woodfine K, Koltowska K, Beechey CV, Peters J, et al. Regulation of alternative polyadenylation by genomic imprinting. Genes Dev. 2008;22:1141–6. Scholar
  11. 11.
    Danckwardt S, Kaufmann I, Gentzel M, Foerstner KU, Gantzert A-S, Gehring NH, et al. Splicing factors stimulate polyadenylation via USEs at non-canonical 3′ end formation signals. EMBO J. 2007;26:2658–69. Available: Scholar
  12. 12.
    Hall-Pogar T, Liang S, Hague LK, Lutz CS. Specific trans-acting proteins interact with auxiliary RNA polyadenylation elements in the COX-2 3′-UTR. RNA. 2007;13:1103–15. Scholar
  13. 13.
    Tian B, Pan Z, Lee JY. Widespread mRNA polyadenylation events in introns indicate dynamic interplay between polyadenylation and splicing. Genome Res. 2007;17:156–65. Scholar
  14. 14.
    Meyer S, Temme C, Wahle E. Messenger RNA turnover in eukaryotes: pathways and enzymes. Crit Rev Biochem Mol Biol. 2004;39:197–216. Scholar
  15. 15.
    Weidmann CA, Raynard NA, Blewett NH, Van Etten J, Goldstrohm AC. The RNA binding domain of Pumilio antagonizes poly-adenosine binding protein and accelerates deadenylation. RNA. 2014;20:1298–319. Scholar
  16. 16.
    Furuichi Y, LaFiandra A, Shatkin AJ. 5′-Terminal structure and mRNA stability. Nature. 1977;266:235–9. Scholar
  17. 17.
    Shimotohno K, Kodama Y, Hashimoto J, Miura KI. Importance of 5′-terminal blocking structure to stabilize mRNA in eukaryotic protein synthesis. Proc Natl Acad Sci U S A. 1977;74:2734–8. Available: Scholar
  18. 18.
    Murthy KGK, Park P, Manley JL. A nuclear micrococcal-sensitive, ATP-dependent exoribonuclease degrades uncapped but not capped RNA substratesx. Nucleic Acids Res. 1991;19:2685–92. Scholar
  19. 19.
    Muthukrishnan S, Both GW, Furuichi Y, Shatkin AJ. 5′-Terminal 7-methylguanosine in eukaryotic mRNA is required for translation. Nature. 1975;255:33–7. Available: Scholar
  20. 20.
    Gillian-Daniel DL, Gray NK, Aström J, Barkoff A, Wickens M. Modifications of the 5′ cap of mRNAs during Xenopus oocyte maturation: independence from changes in poly(A) length and impact on translation. Mol Cell Biol. 1998;18:6152–63. Available: Scholar
  21. 21.
    Konarska MM, Padgett RA, Sharp PA. Recognition of cap structure in splicing in vitro of mRNA precursors. Cell. 1984;38:731–6. Available: Scholar
  22. 22.
    Edery I, Sonenberg N. Cap-dependent RNA splicing in a HeLa nuclear extract. Proc Natl Acad Sci U S A. 1985;82:7590–4. Available: Scholar
  23. 23.
    Flaherty SM, Fortes P, Izaurralde E, Mattaj IW, Gilmartin GM. Participation of the nuclear cap binding complex in pre-mRNA 3′ processing. Proc Natl Acad Sci U S A. 1997;94:11893–8. Available: Scholar
  24. 24.
    Jarmolowski A, Boelens WC, Izaurralde E, Mattaj IW. Nuclear export of different classes of RNA is mediated by specific factors. J Cell Biol. 1994;124:627–35. Available: Scholar
  25. 25.
    Fresco LD, Buratowski S. Conditional mutants of the yeast mRNA capping enzyme show that the cap enhances, but is not required for, mRNA splicing. RNA. 1996;2:584–96. Available: Scholar
  26. 26.
    Glover-Cutter K, Kim S, Espinosa J, Bentley DL. RNA polymerase II pauses and associates with pre-mRNA processing factors at both ends of genes. Nat Struct Mol Biol. 2008;15:71–8. Scholar
  27. 27.
    Shatkin AJ. Capping of eucaryotic mRNAs. Cell. 1976;9:645–53. Scholar
  28. 28.
    Nojima T, Hirose T, Kimura H, Hagiwara M. The interaction between cap-binding complex and RNA export factor is required for intronless mRNA export. J Biol Chem. 2007;282:15645–51. Scholar
  29. 29.
    Cheng H, Dufu K, Lee C-S, Hsu JL, Dias A, Reed R. Human mRNA export machinery recruited to the 5′ end of mRNA. Cell. 2006;127:1389–400. Scholar
  30. 30.
    Sato H, Maquat LE. Remodeling of the pioneer translation initiation complex involves translation and the karyopherin importin beta. Genes Dev. 2009;23:2537–50. Scholar
  31. 31.
    Dias SMG, Wilson KF, Rojas KS, Ambrosio ALB, Cerione RA. The molecular basis for the regulation of the cap-binding complex by the importins. Nat Struct Mol Biol. 2009;16:930–7. Scholar
  32. 32.
    Schwartz DC, Parker R. mRNA decapping in yeast requires dissociation of the cap binding protein, eukaryotic translation initiation factor 4E. Mol Cell Biol. 2000;20:7933–42. Available: Scholar
  33. 33.
    Grudzien E, Kalek M, Jemielity J, Darzynkiewicz E, Rhoads RE. Differential inhibition of mRNA degradation pathways by novel cap analogs. J Biol Chem. 2006;281:1857–67. Scholar
  34. 34.
    Jiao X, Chang JH, Kilic T, Tong L, Kiledjian M. A mammalian pre-mRNA 5′ end capping quality control mechanism and an unexpected link of capping to pre-mRNA processing. Mol Cell. 2013;50:104–15. Scholar
  35. 35.
    Braun JE, Truffault V, Boland A, Huntzinger E, Chang C-T, Haas G, et al. A direct interaction between DCP1 and XRN1 couples mRNA decapping to 5′ exonucleolytic degradation. Nat Struct Mol Biol Nature Research. 2012;19:1324–31. Scholar
  36. 36.
    Varani G. Exceptionally stable nucleic acid hairpins. Annu Rev Biophys Biomol Struct. 1995;24:379–404. Scholar
  37. 37.
    Emory SA, Bouvet P, Belasco JG. A 5′-terminal stem-loop structure can stabilize mRNA in Escherichia coli. Genes Dev. 1992;6:135–48. Available: Scholar
  38. 38.
    Hambraeus G, Karhumaa K, Rutberg B. A 5′ stem–loop and ribosome binding but not translation are important for the stability of Bacillus subtilis aprE leader mRNA. Microbiol Microbiol Soc. 2002;148:1795–803. Scholar
  39. 39.
    Higgs DC, Shapiro RS, Kindle KL, Stern DB. Small cis-acting sequences that specify secondary structures in a chloroplast mRNA are essential for RNA stability and translation. Mol Cell Biol. 1999;19:8479–91. Available: Scholar
  40. 40.
    Zou Z, Eibl C, Koop H-U. The stem-loop region of the tobacco psbA 5′ UTR is an important determinant of mRNA stability and translation efficiency. Mol Genet Genomics Springer. 2003;269:340–9. Available: Scholar
  41. 41.
    Muslimov IA, Nimmrich V, Hernandez AI, Tcherepanov A, Sacktor TC, Tiedge H. Dendritic transport and localization of protein kinase Mζ mRNA: implications for molecular memory consolidation. J Biol Chem. 2004;279:52613–22. Scholar
  42. 42.
    Chao JA, Patskovsky Y, Patel V, Levy M, Almo SC, Singer RH. ZBP1 recognition of β-actin zipcode induces RNA looping. Genes Dev. 2010;24:148–58. Scholar
  43. 43.
    Kim HH, Lee SJ, Gardiner AS, Perrone-Bizzozero NI, Yoo S. Different motif requirements for the localization zipcode element of β-actin mRNA binding by HuD and ZBP1. Nucleic Acids Res. 2015;43:7432–46. Scholar
  44. 44.
    Kadrmas JL, Ravin AJ, Leontis NB. Relative stabilities of DNA three-way, four-way and five-way junctions (multi-helix junction loops): unpaired nucleotides can be stabilizing or destabilizing. Nucleic Acids Res. 1995;23:2212–22. Available: Scholar
  45. 45.
    Ke A, Zhou K, Ding F, Cate JHD, Doudna JA. A conformational switch controls hepatitis delta virus ribozyme catalysis. Nature. 2004;429:201–5. Scholar
  46. 46.
    Rastogi T, Beattie TL, Olive JE, Collins RA. A long-range pseudoknot is required for activity of the Neurospora VS ribozyme. EMBO J. 1996;15:2820–5. Available: Scholar
  47. 47.
    Theimer CA, Blois CA, Feigon J. Structure of the human telomerase RNA pseudoknot reveals conserved tertiary interactions essential for function. Mol Cell. 2005;17:671–82. Scholar
  48. 48.
    Tang CK, Draper DE. Unusual mRNA pseudoknot structure is recognized by a protein translational repressor. Cell. 1989;57:531–6. Available: Scholar
  49. 49.
    Koritzinsky M, Rouschop KMA, van den Beucken T, Magagnin MG, Savelkouls K, Lambin P, et al. Phosphorylation of eIF2alpha is required for mRNA translation inhibition and survival during moderate hypoxia. Radiother Oncol. 2007;83:353–61. Scholar
  50. 50.
    Spriggs KA, Bushell M, Willis AE. Translational regulation of gene expression during conditions of cell stress. Mol Cell. 2010;40:228–37. Scholar
  51. 51.
    Kedersha NL, Gupta M, Li W, Miller I, Anderson P. RNA-binding proteins TIA-1 and TIAR link the phosphorylation of eIF-2 alpha to the assembly of mammalian stress granules. J Cell Biol. 1999;147:1431–42. Available: Scholar
  52. 52.
    Harding HP, Novoa I, Zhang Y, Zeng H, Wek R, Schapira M, et al. Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell. 2000;6:1099–108. Available: Scholar
  53. 53.
    Mazroui R, Sukarieh R, Bordeleau M-E, Kaufman RJ, Northcote P, Tanaka J, et al. Inhibition of ribosome recruitment induces stress granule formation independently of eukaryotic initiation factor 2alpha phosphorylation. Mol Biol Cell. 2006;17:4212–9. Scholar
  54. 54.
    Kedersha N, Chen S, Gilks N, Li W, Miller IJ, Stahl J, et al. Evidence that ternary complex (eIF2-GTP-tRNA(i)(Met))-deficient preinitiation complexes are core constituents of mammalian stress granules. Mol Biol Cell. 2002;13:195–210. Scholar
  55. 55.
    Kimball SR, Horetsky RL, Ron D, Jefferson LS, Harding HP. Mammalian stress granules represent sites of accumulation of stalled translation initiation complexes. Am J Physiol Cell Physiol. 2003;284:C273–84. Scholar
  56. 56.
    Buchan JR, Yoon J-H, Parker R. Stress-specific composition, assembly and kinetics of stress granules in Saccharomyces cerevisiae. J Cell Sci. 2011;124:228–39. Scholar
  57. 57.
    Kwon S, Zhang Y, Matthias P. The deacetylase HDAC6 is a novel critical component of stress granules involved in the stress response. Genes Dev. 2007;21:3381–94. Scholar
  58. 58.
    Gallouzi IE, Parker F, Chebli K, Maurier F, Labourier E, Barlat I, et al. A novel phosphorylation-dependent RNase activity of GAP-SH3 binding protein: a potential link between signal transduction and RNA stability. Mol Cell Biol. 1998;18:3956–65. Available: Scholar
  59. 59.
    Schmidlin M, Lu M, Leuenberger SA, Stoecklin G, Mallaun M, Gross B, et al. The ARE-dependent mRNA-destabilizing activity of BRF1 is regulated by protein kinase B. EMBO J. 2004;23:4760–9. Scholar
  60. 60.
    Tourrière H, Gallouzi IE, Chebli K, Capony JP, Mouaikel J, van der Geer P, et al. RasGAP-associated endoribonuclease G3Bp: selective RNA degradation and phosphorylation-dependent localization. Mol Cell Biol. 2001;21:7747–60. Scholar
  61. 61.
    Ohn T, Kedersha N, Hickman T, Tisdale S, Anderson P. A functional RNAi screen links O-GlcNAc modification of ribosomal proteins to stress granule and processing body assembly. Nat Cell Biol. 2008;10:1224–31. Scholar
  62. 62.
    Gilks N, Kedersha N, Ayodele M, Shen L, Stoecklin G, Dember LM, et al. Stress granule assembly is mediated by prion-like aggregation of TIA-1. Mol Biol Cell. 2004;15:5383–98. Scholar
  63. 63.
    Colombrita C, Zennaro E, Fallini C, Weber M, Sommacal A, Buratti E, et al. TDP-43 is recruited to stress granules in conditions of oxidative insult. J Neurochem Wiley Online Library. 2009;111:1051–61. Available: Scholar
  64. 64.
    Buchan JR, Parker R. Eukaryotic stress granules: the ins and outs of translation. Mol Cell. 2009;36:932–41. Scholar
  65. 65.
    Laroia G, Cuesta R, Brewer G, Schneider RJ. Control of mRNA decay by heat shock-ubiquitin-proteasome pathway. Science. 1999;284:499–502. Available: Scholar
  66. 66.
    Gowrishankar G, Winzen R, Dittrich-Breiholz O, Redich N, Kracht M, Holtmann H. Inhibition of mRNA deadenylation and degradation by different types of cell stress. Biol Chem. 2006;387:323–7. Scholar
  67. 67.
    Hilgers V, Teixeira D, Parker R. Translation-independent inhibition of mRNA deadenylation during stress in Saccharomyces cerevisiae. RNA. 2006;12:1835–45. Scholar
  68. 68.
    Thomas MG, Martinez Tosar LJ, Desbats MA, Leishman CC, Boccaccio GL. Mammalian Staufen 1 is recruited to stress granules and impairs their assembly. J Cell Sci. 2009;122:563–73. Scholar
  69. 69.
    Tsai N-P, Ho P-C, Wei L-N. Regulation of stress granule dynamics by Grb7 and FAK signalling pathway. EMBO J. 2008;27:715–26. Scholar
  70. 70.
    Rikhvanov EG, Romanova NV, Chernoff YO. Chaperone effects on prion and nonprion aggregates. Prion. 2007;1:217–22. Available: Scholar
  71. 71.
    Raijmakers R, Egberts WV, van Venrooij WJ, Pruijn GJM. Protein–protein interactions between human exosome components support the assembly of RNase PH-type subunits into a six-membered PNPase-like ring. J Mol Biol. 2002;323:653–63. Scholar
  72. 72.
    Schilders G, van Dijk E, Raijmakers R, Pruijn GJM. Cell and molecular biology of the exosome: how to make or break an RNA. Int Rev Cytol. 2006;251:159–208. Scholar
  73. 73.
    Budenholzer L, Cheng CL, Li Y, Hochstrasser M. Proteasome structure and assembly. J Mol Biol. 2017.
  74. 74.
    Houseley J, LaCava J, Tollervey D. RNA-quality control by the exosome. Nat Rev Mol Cell Biol. 2006;7:529–39. Scholar
  75. 75.
    Chen CY, Gherzi R, Ong SE, Chan EL, Raijmakers R, Pruijn GJ, et al. AU binding proteins recruit the exosome to degrade ARE-containing mRNAs. Cell. 2001;107:451–64. Available: Scholar
  76. 76.
    Kowalinski E, Schuller A, Green R, Conti E. Saccharomyces cerevisiae Ski7 Is a GTP-binding protein adopting the characteristic conformation of active translational GTPases. Structure. 2015;23:1336–43. Scholar
  77. 77.
    Frischmeyer PA, van Hoof A, O’Donnell K, Guerrerio AL, Parker R, Dietz HC. An mRNA surveillance mechanism that eliminates transcripts lacking termination codons. Science. 2002;295:2258–61. Scholar
  78. 78.
    Allmang C, Kufel J, Chanfreau G, Mitchell P, Petfalski E, Tollervey D. Functions of the exosome in rRNA, snoRNA and snRNA synthesis. EMBO J. 1999;18:5399–410. Scholar
  79. 79.
    Nagy E, Maquat LE. A rule for termination-codon position within intron-containing genes: when nonsense affects RNA abundance. Trends Biochem Sci. 1998;23:198–9. Available: Scholar
  80. 80.
    Thermann R, Neu-Yilik G, Deters A, Frede U, Wehr K, Hagemeier C, et al. Binary specification of nonsense codons by splicing and cytoplasmic translation. EMBO J. 1998;17:3484–94. Scholar
  81. 81.
    Kashima I, Yamashita A, Izumi N, Kataoka N, Morishita R, Hoshino S, et al. Binding of a novel SMG-1-Upf1-eRF1-eRF3 complex (SURF) to the exon junction complex triggers Upf1 phosphorylation and nonsense-mediated mRNA decay. Genes Dev. 2006;20:355–67. Scholar
  82. 82.
    Melero R, Uchiyama A, Castaño R, Kataoka N, Kurosawa H, Ohno S, et al. Structures of SMG1-UPFs complexes: SMG1 contributes to regulate UPF2-dependent activation of UPF1 in NMD. Structure. 2014;22:1105–19. Scholar
  83. 83.
    Deniaud A, Karuppasamy M, Bock T, Masiulis S, Huard K, Garzoni F, et al. A network of SMG-8, SMG-9 and SMG-1 C-terminal insertion domain regulates UPF1 substrate recruitment and phosphorylation. Nucleic Acids Res. 2015;43:7600–11. Scholar
  84. 84.
    Franks TM, Singh G, Lykke-Andersen J. Upf1 ATPase-dependent mRNP disassembly is required for completion of nonsense- mediated mRNA decay. Cell. 2010;143:938–50. Scholar
  85. 85.
    Fiorini F, Bagchi D, Le Hir H, Croquette V. Human Upf1 is a highly processive RNA helicase and translocase with RNP remodelling activities. Nat Commun. 2015;6:7581. Scholar
  86. 86.
    Huntzinger E, Kashima I, Fauser M, Saulière J, Izaurralde E. SMG6 is the catalytic endonuclease that cleaves mRNAs containing nonsense codons in metazoan. RNA. 2008;14:2609–17. Scholar
  87. 87.
    Eberle AB, Lykke-Andersen S, Mühlemann O, Jensen TH. SMG6 promotes endonucleolytic cleavage of nonsense mRNA in human cells. Nat Struct Mol Biol. 2009;16:49–55. Scholar
  88. 88.
    Loh B, Jonas S, Izaurralde E. The SMG5–SMG7 heterodimer directly recruits the CCR4–NOT deadenylase complex to mRNAs containing nonsense codons via interaction with POP2. Genes Dev. 2013;27:2125–38. Scholar
  89. 89.
    Unterholzner L, Izaurralde E. SMG7 acts as a molecular link between mRNA surveillance and mRNA decay. Mol Cell. 2004;16:587–96. Scholar
  90. 90.
    Hogg JR, Goff SP. Upf1 senses 3′ UTR length to potentiate mRNA decay. Cell. 2010;143:379–89. Available: Scholar
  91. 91.
    Schweingruber C, Rufener SC, Zünd D, Yamashita A, Mühlemann O. Nonsense-mediated mRNA decay – mechanisms of substrate mRNA recognition and degradation in mammalian cells. Biochim Biophys Acta. 1829;2013:612–23. Scholar
  92. 92.
    Avery P, Vicente-Crespo M, Francis D, Nashchekina O, Alonso CR, Palacios IM. Drosophila Upf1 and Upf2 loss of function inhibits cell growth and causes animal death in a Upf3-independent manner. RNA. 2011;17:624–38. Scholar
  93. 93.
    Lou CH, Shao A, Shum EY, Espinoza JL, Huang L, Karam R, et al. Posttranscriptional control of the stem cell and neurogenic programs by the nonsense-mediated RNA decay pathway. Cell Rep. 2014;6:748–64. Scholar
  94. 94.
    Gloggnitzer J, Akimcheva S, Srinivasan A, Kusenda B, Riehs N, Stampfl H, et al. Nonsense-mediated mRNA decay modulates immune receptor levels to regulate plant antibacterial defense. Cell Host Microbe. 2014;16:376–90. Scholar
  95. 95.
    Gardner LB. Nonsense-mediated RNA decay regulation by cellular stress: implications for tumorigenesis. Mol Cancer Res. 2010;8:295–308. Scholar
  96. 96.
    Balistreri G, Horvath P, Schweingruber C, Zünd D, McInerney G, Merits A, et al. The host nonsense-mediated mRNA decay pathway restricts mammalian RNA virus replication. Cell Host Microbe. 2014;16:403–11. Scholar
  97. 97.
    Giorgi C, Yeo GW, Stone ME, Katz DB, Burge C, Turrigiano G, et al. The EJC factor eIF4AIII modulates synaptic strength and neuronal protein expression. Cell. 2007;130:179–91. Scholar
  98. 98.
    Colak D, Ji S-J, Porse BT, Jaffrey SR. Regulation of axon guidance by compartmentalized nonsense-mediated mRNA decay. Cell. 2013;153:1252–65. Scholar
  99. 99.
    Weg-Remers S, Ponta H, Herrlich P, König H. Regulation of alternative pre-mRNA splicing by the ERK MAP-kinase pathway. EMBO J. 2001;20:4194–203. Scholar
  100. 100.
    van der Houven van Oordt W, Diaz-Meco MT, Lozano J, Krainer AR, Moscat J, Cáceres JF. The MKK(3/6)-p38-signaling cascade alters the subcellular distribution of hnRNP A1 and modulates alternative splicing regulation. J Cell Biol. 2000;149:307–16. Available: Scholar
  101. 101.
    Lewis BP, Green RE, Brenner SE. Evidence for the widespread coupling of alternative splicing and nonsense-mediated mRNA decay in humans. Proc Natl Acad Sci U S A. 2003;100:189–92. Scholar
  102. 102.
    Eom T, Zhang C, Wang H, Lay K, Fak J, Noebels JL, et al. NOVA-dependent regulation of cryptic NMD exons controls synaptic protein levels after seizure. elife. 2013;2:e00178. Scholar
  103. 103.
    Winter J, Lehmann T, Krauss S, Trockenbacher A, Kijas Z, Foerster J, et al. Regulation of the MID1 protein function is fine-tuned by a complex pattern of alternative splicing. Hum Genet. 2004;114:541–52. Scholar
  104. 104.
    Sureau A, Gattoni R, Dooghe Y, Stévenin J, Soret J. SC35 autoregulates its expression by promoting splicing events that destabilize its mRNAs. EMBO J. 2001;20:1785–96. Scholar
  105. 105.
    Wilson GM, Sun Y, Sellers J, Lu H, Penkar N, Dillard G, et al. Regulation of AUF1 expression via conserved alternatively spliced elements in the 3′ untranslated region. Mol Cell Biol. 1999;19:4056–64. Available: Scholar
  106. 106.
    Lamba JK, Adachi M, Sun D, Tammur J, Schuetz EG, Allikmets R, et al. Nonsense mediated decay downregulates conserved alternatively spliced ABCC4 transcripts bearing nonsense codons. Hum Mol Genet. 2003;12:99–109. Available: Scholar
  107. 107.
    Jones RB, Wang F, Luo Y, Yu C, Jin C, Suzuki T, et al. The nonsense-mediated decay pathway and mutually exclusive expression of alternatively spliced FGFR2IIIb and -IIIc mRNAs. J Biol Chem. 2001;276:4158–67. Scholar
  108. 108.
    Lareau LF, Brooks AN, Soergel DAW, Meng Q, Brenner SE. The coupling of alternative splicing and nonsense-mediated mRNA decay. Adv Exp Med Biol. 2007;623:190–211. Available: Scholar
  109. 109.
    Morris DR, Geballe AP. Upstream open reading frames as regulators of mRNA translation. Mol Cell Biol. 2000;20:8635–42. Scholar
  110. 110.
    Kozak M. Structural features in eukaryotic mRNAs that modulate the initiation of translation. J Biol Chem. 1991;266:19867–70. Available: Scholar
  111. 111.
    Matsui M, Yachie N, Okada Y, Saito R, Tomita M. Bioinformatic analysis of post-transcriptional regulation by uORF in human and mouse. FEBS Lett. 2007;581:4184–8. Scholar
  112. 112.
    Calvo SE, Pagliarini DJ, Mootha VK. Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans. Proc Natl Acad Sci U S A. 2009;106:7507–12. Scholar
  113. 113.
    Mendell JT, Sharifi NA, Meyers JL, Martinez-Murillo F, Dietz HC. Nonsense surveillance regulates expression of diverse classes of mammalian transcripts and mutes genomic noise. Nat Genet. 2004;36:1073–8. Scholar
  114. 114.
    Ramani AK, Nelson AC, Kapranov P, Bell I, Gingeras TR, Fraser AG. High resolution transcriptome maps for wild-type and nonsense-mediated decay-defective Caenorhabditis elegans. Genome Biol. 2009;10:R101. Scholar
  115. 115.
    He F, Li X, Spatrick P, Casillo R, Dong S, Jacobson A. Genome-wide analysis of mRNAs regulated by the nonsense-mediated and 5′ to 3′ mRNA decay pathways in yeast. Mol Cell. 2003;12:1439–52. Scholar
  116. 116.
    van Hoof A, Frischmeyer PA, Dietz HC, Parker R. Exosome-mediated recognition and degradation of mRNAs lacking a termination codon. Science. 2002;295:2262–4. Scholar
  117. 117.
    Karzai AW, Roche ED, Sauer RT. The SsrA-SmpB system for protein tagging, directed degradation and ribosome rescue. Nat Struct Biol. 2000;7:449–55. Scholar
  118. 118.
    Benard L, Carroll K, Valle RC, Masison DC, Wickner RB. The ski7 antiviral protein is an EF1-alpha homolog that blocks expression of non-Poly(A) mRNA in Saccharomyces cerevisiae. J Virol. 1999;73:2893–900. Available: Scholar
  119. 119.
    Anderson JS, Parker RP. The 3′ to 5′ degradation of yeast mRNAs is a general mechanism for mRNA turnover that requires the SKI2 DEVH box protein and 3′ to 5′ exonucleases of the exosome complex. EMBO J. 1998;17:1497–506. Scholar
  120. 120.
    Caponigro G, Parker R. Multiple functions for the poly(A)-binding protein in mRNA decapping and deadenylation in yeast. Genes Dev. 1995;9:2421–32. Scholar
  121. 121.
    Doma MK, Parker R. Endonucleolytic cleavage of eukaryotic mRNAs with stalls in translation elongation. Nature. 2006;440:561–4. Scholar
  122. 122.
    Tollervey D. Molecular biology: RNA lost in translation. Nature. 2006;440:425–6. Scholar
  123. 123.
    Clement SL, Lykke-Andersen J. No mercy for messages that mess with the ribosome. Nat Struct Mol Biol. 2006;13:299–301. Scholar
  124. 124.
    Young SK, Palam LR, Wu C, Sachs MS, Wek RC. Ribosome elongation stall directs gene-specific translation in the integrated stress response. J Biol Chem. 2016;291:6546–58. Scholar
  125. 125.
    Passos DO, Doma MK, Shoemaker CJ, Muhlrad D, Green R, Weissman J, et al. Analysis of Dom34 and its function in no-go decay. Mol Biol Cell. 2009;20:3025–32. Scholar
  126. 126.
    Graille M, Chaillet M, van Tilbeurgh H. Structure of yeast Dom34: a protein related to translation termination factor Erf1 and involved in No-Go decay. J Biol Chem. 2008;283:7145–54. Scholar
  127. 127.
    Lee HH. Structural and functional insights into Dom34, a key component of No-Go mRNA decay, and structure of a metal Ion-Bound IS200 transposase. Mol Cell. 2007;27(6):938–50. Available: Scholar
  128. 128.
    Carr-Schmid A, Pfund C, Craig EA, Kinzy TG. Novel G-protein complex whose requirement is linked to the translational status of the cell. Mol Cell Biol. 2002;22:2564–74. Available: Scholar
  129. 129.
    Protzel A, Morris AJ. Gel chromatographic analysis of nascent globin chains. Evidence of nonuniform size distribution. J Biol Chem. 1974;249:4594–600. Available: Scholar
  130. 130.
    Beelman CA, Parker R. Differential effects of translational inhibition in cis and in trans on the decay of the unstable yeast MFA2 mRNA. J Biol Chem. 1994;269:9687–92. Available: Scholar
  131. 131.
    Nagai K, Oubridge C, Kuglstatter A, Menichelli E, Isel C, Jovine L. Structure, function and evolution of the signal recognition particle. EMBO J. 2003;22:3479–85. Scholar
  132. 132.
    Wang Z, Sachs MS. Ribosome stalling is responsible for arginine-specific translational attenuation in Neurospora crassa. Mol Cell Biol. 1997;17:4904–13. Available: Scholar
  133. 133.
    Chen CY, Shyu AB. AU-rich elements: characterization and importance in mRNA degradation. Trends Biochem Sci. 1995;20:465–70. Available: Scholar
  134. 134.
    Shaw G, Kamen R. A conserved AU sequence from the 3′ untranslated region of GM-CSF mRNA mediates selective mRNA degradation. Cell. 1986;46:659–67. Available: Scholar
  135. 135.
    Loflin P, Chen CY, Shyu AB. Unraveling a cytoplasmic role for hnRNP D in the in vivo mRNA destabilization directed by the AU-rich element. Genes Dev. 1999;13:1884–97. Available: Scholar
  136. 136.
    Sarkar B, Xi Q, He C, Schneider RJ. Selective degradation of AU-rich mRNAs promoted by the p37 AUF1 protein isoform. Mol Cell Biol. 2003;23:6685–93. Available: Scholar
  137. 137.
    Lal A, Mazan-Mamczarz K, Kawai T, Yang X, Martindale JL, Gorospe M. Concurrent versus individual binding of HuR and AUF1 to common labile target mRNAs. EMBO J. 2004;23:3092–102. Scholar
  138. 138.
    Raineri I, Wegmueller D, Gross B, Certa U, Moroni C. Roles of AUF1 isoforms, HuR and BRF1 in ARE-dependent mRNA turnover studied by RNA interference. Nucleic Acids Res. 2004;32:1279–88. Scholar
  139. 139.
    Carballo E, Gilkeson GS, Blackshear PJ. Bone marrow transplantation reproduces the tristetraprolin-deficiency syndrome in recombination activating gene-2 (−/−) mice. Evidence that monocyte/macrophage progenitors may be responsible for TNFalpha overproduction. J Clin Invest. 1997;100:986–95. Scholar
  140. 140.
    Carballo E, Lai WS, Blackshear PJ. Evidence that tristetraprolin is a physiological regulator of granulocyte-macrophage colony-stimulating factor messenger RNA deadenylation and stability. Blood. 2000;95:1891–9. Available: Scholar
  141. 141.
    Ogilvie RL, Abelson M, Hau HH, Vlasova I, Blackshear PJ, Bohjanen PR. Tristetraprolin down-regulates IL-2 gene expression through AU-rich element-mediated mRNA decay. J Immunol. 2005;174:953–61. Available: Scholar
  142. 142.
    Carballo E, Lai WS, Blackshear PJ. Feedback inhibition of macrophage tumor necrosis factor-alpha production by tristetraprolin. Science. 1998;281:1001–5. Available: Scholar
  143. 143.
    Lai WS, Blackshear PJ. Interactions of CCCH zinc finger proteins with mRNA: tristetraprolin-mediated AU-rich element-dependent mRNA degradation can occur in the absence of a poly(A) tail. J Biol Chem. 2001;276:23144–54. Scholar
  144. 144.
    Lai WS, Kennington EA, Blackshear PJ. Tristetraprolin and its family members can promote the cell-free deadenylation of AU-rich element-containing mRNAs by poly(A) ribonuclease. Mol Cell Biol. 2003;23:3798–812. Scholar
  145. 145.
    Lai WS, Carballo E, Strum JR, Kennington EA, Phillips RS, Blackshear PJ. Evidence that tristetraprolin binds to AU-rich elements and promotes the deadenylation and destabilization of tumor necrosis factor alpha mRNA. Mol Cell Biol. 1999;19:4311–23. Available: Scholar
  146. 146.
    Sawaoka H, Dixon DA, Oates JA, Boutaud O. Tristetraprolin binds to the 3′-untranslated region of cyclooxygenase-2 mRNA: a polyadenylation variant in a cancer cell line lacks the binding site. J Biol Chem. 2003;278:13928–35. Scholar
  147. 147.
    Stoecklin G, Ming XF, Looser R, Moroni C. Somatic mRNA turnover mutants implicate tristetraprolin in the interleukin-3 mRNA degradation pathway. Mol Cell Biol. 2000;20:3753–63. Available: Scholar
  148. 148.
    Wilson GM, Brewer G. The search for trans-acting factors controlling messenger RNA decay. Prog Nucleic Acid Res Mol Biol. 1999;62:257–91. Available: Scholar
  149. 149.
    Wilson T, Treisman R. Removal of poly(A) and consequent degradation of c-fos mRNA facilitated by 3′ AU-rich sequences. Nature. 1988;336:396–9. Scholar
  150. 150.
    Shyu AB, Belasco JG, Greenberg ME. Two distinct destabilizing elements in the c-fos message trigger deadenylation as a first step in rapid mRNA decay. Genes Dev. 1991;5:221–31. Available: Scholar
  151. 151.
    Brewer G, Ross J. Poly(A) shortening and degradation of the 3′ A+U-rich sequences of human c-myc mRNA in a cell-free system. Mol Cell Biol. 1988;8:1697–708. Scholar
  152. 152.
    Mukherjee D, Gao M, O’Connor JP, Raijmakers R, Pruijn G, Lutz CS, et al. The mammalian exosome mediates the efficient degradation of mRNAs that contain AU-rich elements. EMBO J. 2002;21:165–74. Scholar
  153. 153.
    Gherzi R, Lee K-Y, Briata P, Wegmüller D, Moroni C, Karin M, et al. A KH domain RNA binding protein, KSRP, promotes ARE-directed mRNA turnover by recruiting the degradation machinery. Mol Cell. 2004;14:571–83. Scholar
  154. 154.
    Kedersha N, Stoecklin G, Ayodele M, Yacono P, Lykke-Andersen J, Fritzler MJ, et al. Stress granules and processing bodies are dynamically linked sites of mRNP remodeling. J Cell Biol. 2005;169:871–84. Scholar
  155. 155.
    Kedersha N, Anderson P. Stress granules: sites of mRNA triage that regulate mRNA stability and translatability. Biochem Soc Trans. 2002;30:963–9.CrossRefPubMedGoogle Scholar
  156. 156.
    Levy NS, Chung S, Furneaux H, Levy AP. Hypoxic stabilization of vascular endothelial growth factor mRNA by the RNA-binding protein HuR. J Biol Chem. 1998;273:6417–23. Available: Scholar
  157. 157.
    Peng SS, Chen CY, Xu N, Shyu AB. RNA stabilization by the AU-rich element binding protein, HuR, an ELAV protein. EMBO J. 1998;17:3461–70. Scholar
  158. 158.
    Rodriguez-Pascual F, Hausding M, Ihrig-Biedert I, Furneaux H, Levy AP, Förstermann U, et al. Complex contribution of the 3′-untranslated region to the expressional regulation of the human inducible nitric-oxide synthase gene. Involvement of the RNA-binding protein HuR. J Biol Chem. 2000;275:26040–9. Scholar
  159. 159.
    JLE D, Wait R, Mahtani KR, Sully G, Clark AR, Saklatvala J. The 3′ untranslated region of tumor necrosis factor alpha mRNA is a target of the mRNA-stabilizing factor HuR. Mol Cell Biol. 2005;25:3400. Scholar
  160. 160.
    Kim YK, Furic L, Desgroseillers L, Maquat LE. Mammalian Staufen1 recruits Upf1 to specific mRNA 3′UTRs so as to elicit mRNA decay. Cell. 2005;120:195–208. Scholar
  161. 161.
    Kim YK, Furic L, Parisien M, Major F, DesGroseillers L, Maquat LE. Staufen1 regulates diverse classes of mammalian transcripts. EMBO J. 2007;26:2670–81. Scholar
  162. 162.
    Gong C, Maquat LE. lncRNAs transactivate STAU1-mediated mRNA decay by duplexing with 3′ UTRs via Alu elements. Nature. 2011;470:284–8. Scholar
  163. 163.
    Gong C, Kim YK, Woeller CF, Tang Y, Maquat LE. SMD and NMD are competitive pathways that contribute to myogenesis: effects on PAX3 and myogenin mRNAs. Genes Dev. 2009;23:54–66. Scholar
  164. 164.
    Cai X, Hagedorn CH, Cullen BR. Human microRNAs are processed from capped, polyadenylated transcripts that can also function as mRNAs. RNA. 2004;10:1957–66. Scholar
  165. 165.
    Lee Y, Kim M, Han J, Yeom K-H, Lee S, Baek SH, et al. MicroRNA genes are transcribed by RNA polymerase II. EMBO J. 2004;23:4051–60. Scholar
  166. 166.
    Lee Y, Ahn C, Han J, Choi H, Kim J, Yim J, et al. The nuclear RNase III Drosha initiates microRNA processing. Nature. 2003;425:415–9. Scholar
  167. 167.
    Gregory RI, Chendrimada TP, Shiekhattar R. MicroRNA biogenesis: isolation and characterization of the microprocessor complex. Methods Mol Biol. 2006;342:33–47. Scholar
  168. 168.
    Murchison EP, Hannon GJ. miRNAs on the move: miRNA biogenesis and the RNAi machinery. Curr Opin Cell Biol. 2004;16:223–9. Scholar
  169. 169.
    Lund E, Dahlberg JE. Substrate selectivity of exportin 5 and Dicer in the biogenesis of microRNAs. Cold Spring Harb Symp Quant Biol. 2006;71:59–66. Scholar
  170. 170.
    Khvorova A, Reynolds A, Jayasena SD. Functional siRNAs and miRNAs exhibit strand bias. Cell. 2003;115:209–16. Available: Scholar
  171. 171.
    Schwarz DS, Hutvágner G, Du T, Xu Z, Aronin N, Zamore PD. Asymmetry in the assembly of the RNAi enzyme complex. Cell. 2003;115:199–208. Available: Scholar
  172. 172.
    Hausser J, Syed AP, Bilen B, Zavolan M. Analysis of CDS-located miRNA target sites suggests that they can effectively inhibit translation. Genome Res. 2013;23:604–15. Scholar
  173. 173.
    Fang Z, Rajewsky N. The impact of miRNA target sites in coding sequences and in 3′UTRs. PLoS One. 2011;6:e18067. Scholar
  174. 174.
    Alemán LM, Doench J, Sharp PA. Comparison of siRNA-induced off-target RNA and protein effects. RNA. 2007;13:385–95. Scholar
  175. 175.
    Eulalio A, Huntzinger E, Izaurralde E. GW182 interaction with Argonaute is essential for miRNA-mediated translational repression and mRNA decay. Nat Struct Mol Biol. 2008;15:346–53. Scholar
  176. 176.
    Behm-Ansmant I, Rehwinkel J, Doerks T, Stark A, Bork P, Izaurralde E. mRNA degradation by miRNAs and GW182 requires both CCR4:NOT deadenylase and DCP1:DCP2 decapping complexes. Genes Dev. 2006;20:1885–98. Scholar
  177. 177.
    Wu L, Fan J, Belasco JG. MicroRNAs direct rapid deadenylation of mRNA. Proc Natl Acad Sci U S A. 2006;103:4034–9. Scholar
  178. 178.
    Stoecklin G, Lu M, Rattenbacher B, Moroni C. A constitutive decay element promotes tumor necrosis factor alpha mRNA degradation via an AU-rich element-independent pathway. Mol Cell Biol. 2003;23:3506–15. Available: Scholar
  179. 179.
    Leppek K, Schott J, Reitter S, Poetz F, Hammond MC, Stoecklin G. Roquin promotes constitutive mRNA decay via a conserved class of stem-loop recognition motifs. Cell. 2013;153:869–81. Scholar
  180. 180.
    Tan D, Zhou M, Kiledjian M, Tong L. The ROQ domain of Roquin recognizes mRNA constitutive-decay element and double-stranded RNA. Nat Struct Mol Biol. 2014;21:679–85. Scholar
  181. 181.
    Marzluff WF, Wagner EJ, Duronio RJ. Metabolism and regulation of canonical histone mRNAs: life without a poly(A) tail. Nat Rev Genet. 2008;9:843–54. Scholar
  182. 182.
    Mullen TE, Marzluff WF. Degradation of histone mRNA requires oligouridylation followed by decapping and simultaneous degradation of the mRNA both 5′ to 3′ and 3′ to 5′. Genes Dev. 2008;22:50–65. Scholar
  183. 183.
    Kaygun H, Marzluff WF. Regulated degradation of replication-dependent histone mRNAs requires both ATR and Upf1. Nat Struct Mol Biol. 2005;12:794–800. Scholar
  184. 184.
    Eulalio A, Behm-Ansmant I, Schweizer D, Izaurralde E. P-body formation is a consequence, not the cause, of RNA-mediated gene silencing. Mol Cell Biol. 2007;27:3970–81. Scholar
  185. 185.
    Teixeira D, Sheth U, Valencia-Sanchez MA, Brengues M, Parker R. Processing bodies require RNA for assembly and contain nontranslating mRNAs. RNA. 2005;11:371–82. Scholar
  186. 186.
    Liu J, Valencia-Sanchez MA, Hannon GJ, Parker R. MicroRNA-dependent localization of targeted mRNAs to mammalian P-bodies. Nat Cell Biol. 2005;7:719–23. Scholar
  187. 187.
    Brengues M, Teixeira D, Parker R. Movement of eukaryotic mRNAs between polysomes and cytoplasmic processing bodies. Science. 2005;310:486–9. Scholar
  188. 188.
    Koritzinsky M, Magagnin MG, van den Beucken T, Seigneuric R, Savelkouls K, Dostie J, et al. Gene expression during acute and prolonged hypoxia is regulated by distinct mechanisms of translational control. EMBO J. 2006;25:1114–25. Scholar
  189. 189.
    Coller J, Parker R. General translational repression by activators of mRNA decapping. Cell. 2005;122:875–86. Scholar
  190. 190.
    Parker R, Sheth U. P bodies and the control of mRNA translation and degradation. Mol Cell. 2007;25:635–46. Scholar
  191. 191.
    Holmes LEA, Campbell SG, De Long SK, Sachs AB, Ashe MP. Loss of translational control in yeast compromised for the major mRNA decay pathway. Mol Cell Biol. 2004;24:2998–3010. Available: Scholar
  192. 192.
    Sheth U, Parker R. Decapping and decay of messenger RNA occur in cytoplasmic processing bodies. Science. 2003;300:805–8. Scholar
  193. 193.
    Cougot N, Babajko S, Séraphin B. Cytoplasmic foci are sites of mRNA decay in human cells. J Cell Biol. 2004;165:31–40. Scholar
  194. 194.
    Bhattacharyya SN, Habermacher R, Martine U, Closs EI, Filipowicz W. Relief of microRNA-mediated translational repression in human cells subjected to stress. Cell. 2006;125:1111–24. Scholar
  195. 195.
    D’Lima NG, Ma J, Winkler L, Chu Q, Loh KH, Corpuz EO, et al. A human microprotein that interacts with the mRNA decapping complex. Nat Chem Biol. 2017;13:174–80. Scholar
  196. 196.
    Cougot N, Daguenet E, Baguet A, Cavalier A, Thomas D, Bellaud P, et al. Overexpression of MLN51 triggers P-body disassembly and formation of a new type of RNA granules. J Cell Sci. 2014;127:4692–701. Scholar
  197. 197.
    Aulas A, Vande VC. Alterations in stress granule dynamics driven by TDP-43 and FUS: a link to pathological inclusions in ALS? Front Cell Neurosci. 2015;9:423. Scholar
  198. 198.
    Zinszner H, Sok J, Immanuel D, Yin Y, Ron D. TLS (FUS) binds RNA in vivo and engages in nucleo-cytoplasmic shuttling. J Cell Sci. 1997;110(Pt 15):1741–50. Available: Scholar
  199. 199.
    Åman P, Panagopoulos I, Lassen C, Fioretos T, Mencinger M, Toresson H, et al. Expression patterns of the human sarcoma-associated genes FUS and EWS and the genomic structure of FUS. Genomics. 1996;37:1–8. Scholar
  200. 200.
    Ling S-C, Polymenidou M, Cleveland DW. Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis. Neuron. 2013;79:416–38. Scholar
  201. 201.
    Kwiatkowski TJ Jr, Bosco DA, Leclerc AL, Tamrazian E, Vanderburg CR, Russ C, et al. Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science. 2009;323:1205–8. Scholar
  202. 202.
    Dormann D, Rodde R, Edbauer D, Bentmann E, Fischer I, Hruscha A, et al. ALS-associated fused in sarcoma (FUS) mutations disrupt transportin-mediated nuclear import. EMBO J. 2010;29:2841–57. Scholar
  203. 203.
    Van Deerlin VM, Leverenz JB, Bekris LM, Bird TD, Yuan W, Elman LB, et al. TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis. Lancet Neurol. 2008;7:409–16. Scholar
  204. 204.
    Ayala YM, Zago P, D’Ambrogio A, Xu Y-F, Petrucelli L, Buratti E, et al. Structural determinants of the cellular localization and shuttling of TDP-43. J Cell Sci. 2008;121:3778–85. Scholar
  205. 205.
    Zhang ZC, Chook YM. Structural and energetic basis of ALS-causing mutations in the atypical proline-tyrosine nuclear localization signal of the Fused in Sarcoma protein (FUS). Proc Natl Acad Sci U S A. 2012;109:12017–21. Scholar
  206. 206.
    McDonald KK, Aulas A, Destroismaisons L, Pickles S, Beleac E, Camu W, et al. TAR DNA-binding protein 43 (TDP-43) regulates stress granule dynamics via differential regulation of G3BP and TIA-1. Hum Mol Genet. 2011;20:1400–10. Scholar
  207. 207.
    Liu-Yesucevitz L, Bilgutay A, Zhang Y-J, Vanderweyde T, Vanderwyde T, Citro A, et al. Tar DNA binding protein-43 (TDP-43) associates with stress granules: analysis of cultured cells and pathological brain tissue. PLoS One. 2010;5:e13250. Scholar
  208. 208.
    Parker SJ, Meyerowitz J, James JL, Liddell JR, Crouch PJ, Kanninen KM, et al. Endogenous TDP-43 localized to stress granules can subsequently form protein aggregates. Neurochem Int. 2012;60:415–24. Scholar
  209. 209.
    Polymenidou M, Lagier-Tourenne C, Hutt KR, Huelga SC, Moran J, Liang TY, et al. Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43. Nat Neurosci. 2011;14:459–68. Scholar
  210. 210.
    Lagier-Tourenne C, Polymenidou M, Hutt KR, Vu AQ, Baughn M, Huelga SC, et al. Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs. Nat Neurosci. 2012;15:1488–97. Scholar
  211. 211.
    Voigt A, Herholz D, Fiesel FC, Kaur K, Müller D, Karsten P, et al. TDP-43-mediated neuron loss in vivo requires RNA-binding activity. PLoS One. 2010;5:e12247. Scholar
  212. 212.
    Daigle JG, Lanson NA Jr, Smith RB, Casci I, Maltare A, Monaghan J, et al. RNA-binding ability of FUS regulates neurodegeneration, cytoplasmic mislocalization and incorporation into stress granules associated with FUS carrying ALS-linked mutations. Hum Mol Genet. 2013;22:1193–205. Scholar
  213. 213.
    Johnson JO, Pioro EP, Boehringer A, Chia R, Feit H, Renton AE, et al. Mutations in the Matrin 3 gene cause familial amyotrophic lateral sclerosis. Nat Neurosci. 2014;17:664–6. Scholar
  214. 214.
    Kim HJ, Kim NC, Wang Y-D, Scarborough EA, Moore J, Diaz Z, et al. Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature. 2013;495:467–73. Scholar
  215. 215.
    Mackenzie IR, Nicholson AM, Sarkar M, Messing J, Purice MD, Pottier C, et al. TIA1 mutations in amyotrophic lateral sclerosis and frontotemporal dementia promote phase separation and alter stress granule dynamics. Neuron. 2017;95:808–816.e9. Scholar
  216. 216.
    Bug M, Meyer H. Expanding into new markets—VCP/p97 in endocytosis and autophagy. J Struct Biol. 2012;179:78–82. Available: Scholar
  217. 217.
    Dantuma NP, Acs K, Luijsterburg MS. Should I stay or should I go: VCP/p97-mediated chromatin extraction in the DNA damage response. Exp Cell Res. 2014;329:9–17. Scholar
  218. 218.
    Buchan JR, Kolaitis R-M, Taylor JP, Parker R. Eukaryotic stress granules are cleared by autophagy and Cdc48/VCP function. Cell. 2013;153:1461–74. Scholar
  219. 219.
    Koppers M, van Blitterswijk MM, Vlam L, Rowicka PA, van PWJ V, EJN G, et al. VCP mutations in familial and sporadic amyotrophic lateral sclerosis. Neurobiol Aging. 2012;33:837.e7–13. Scholar
  220. 220.
    Treangen TJ, Salzberg SL. Repetitive DNA and next-generation sequencing: computational challenges and solutions. Nat Rev Genet. 2011;13:36–46. Scholar
  221. 221.
    Echeverria GV, Cooper TA. RNA-binding proteins in microsatellite expansion disorders: mediators of RNA toxicity. Brain Res. 2012;1462:100–11. Scholar
  222. 222.
    Mohan A, Goodwin M, Swanson MS. RNA-protein interactions in unstable microsatellite diseases. Brain Res. 2014;1584:3–14. Scholar
  223. 223.
    Kiliszek A, Rypniewski W. Structural studies of CNG repeats. Nucleic Acids Res. 2014;42:8189–99. Scholar
  224. 224.
    Napierała M, Krzyzosiak WJ. CUG repeats present in myotonin kinase RNA form metastable “slippery” hairpins. J Biol Chem. 1997;272:31079–85. Available: Scholar
  225. 225.
    Haeusler AR, Donnelly CJ, Periz G, Simko EAJ, Shaw PG, Kim M-S, et al. C9orf72 nucleotide repeat structures initiate molecular cascades of disease. Nature. 2014;507:195–200. Scholar
  226. 226.
    Burge S, Parkinson GN, Hazel P, Todd AK, Neidle S. Quadruplex DNA: sequence, topology and structure. Nucleic Acids Res. 2006;34:5402–15. Scholar
  227. 227.
    Paeschke K, Simonsson T, Postberg J, Rhodes D, Lipps HJ. Telomere end-binding proteins control the formation of G-quadruplex DNA structures in vivo. Nat Struct Mol Biol. 2005;12:847–54. Scholar
  228. 228.
    Renton AE, Majounie E, Waite A, Simón-Sánchez J, Rollinson S, Gibbs JR, et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron. 2011;72:257–68. Scholar
  229. 229.
    DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron. 2011;72:245–56. Scholar
  230. 230.
    Rutherford NJ, Heckman MG, Dejesus-Hernandez M, Baker MC, Soto-Ortolaza AI, Rayaprolu S, et al. Length of normal alleles of C9ORF72 GGGGCC repeat do not influence disease phenotype. Neurobiol Aging. 2012;33:2950.e5–7. Scholar
  231. 231.
    van Blitterswijk M, DeJesus-Hernandez M, Niemantsverdriet E, Murray ME, Heckman MG, Diehl NN, 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;12:978–88. Scholar
  232. 232.
    Fratta P, Mizielinska S, Nicoll AJ, Zloh M, Fisher EMC, Parkinson G, et al. C9orf72 hexanucleotide repeat associated with amyotrophic lateral sclerosis and frontotemporal dementia forms RNA G-quadruplexes. Sci Rep. 2012;2:1016. Scholar
  233. 233.
    Reddy K, Zamiri B, Stanley SYR, Macgregor RB Jr, Pearson CE. 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;288:9860–6. Scholar
  234. 234.
    Reddy K, Tam M, Bowater RP, Barber M, Tomlinson M, Nichol Edamura K, et al. Determinants of R-loop formation at convergent bidirectionally transcribed trinucleotide repeats. Nucleic Acids Res. 2011;39:1749–62. Scholar
  235. 235.
    Lin Y, Dent SYR, Wilson JH, Wells RD, Napierala M. R loops stimulate genetic instability of CTG.CAG repeats. Proc Natl Acad Sci U S A. 2010;107:692–7. Scholar
  236. 236.
    Belotserkovskii BP, Mirkin SM, Hanawalt PC. DNA sequences that interfere with transcription: implications for genome function and stability. Chem Rev. 2013;113:8620–37. Scholar
  237. 237.
    Groh M, Lufino MMP, Wade-Martins R, Gromak N. R-loops associated with triplet repeat expansions promote gene silencing in Friedreich ataxia and fragile X syndrome. PLoS Genet. 2014;10:e1004318. Scholar
  238. 238.
    Huertas P, Aguilera A. Cotranscriptionally formed DNA:RNA hybrids mediate transcription elongation impairment and transcription-associated recombination. Mol Cell. 2003;12:711–21. Available: Scholar
  239. 239.
    Castellano-Pozo M, Santos-Pereira JM, Rondón AG, Barroso S, Andújar E, Pérez-Alegre M, et al. R loops are linked to histone H3 S10 phosphorylation and chromatin condensation. Mol Cell. 2013;52:583–90. Scholar
  240. 240.
    Skourti-Stathaki K, Proudfoot NJ, Gromak N. Human senataxin resolves RNA/DNA hybrids formed at transcriptional pause sites to promote Xrn2-dependent termination. Mol Cell. 2011;42:794–805. Scholar
  241. 241.
    Walker C, Herranz-Martin S, Karyka E, Liao C, Lewis K, Elsayed W, et al. C9orf72 expansion disrupts ATM-mediated chromosomal break repair. Nat Neurosci. 2017;20:1225–35. Scholar
  242. 242.
    de Mezer M, Wojciechowska M, Napierala M, Sobczak K, Krzyzosiak WJ. Mutant CAG repeats of Huntingtin transcript fold into hairpins, form nuclear foci and are targets for RNA interference. Nucleic Acids Res. 2011;39:3852–63. Scholar
  243. 243.
    Conlon EG, Lu L, Sharma A, Yamazaki T, Tang T, Shneider NA, et al. The C9ORF72 GGGGCC expansion forms RNA G-quadruplex inclusions and sequesters hnRNP H to disrupt splicing in ALS patient brains. eLife. 2016;5:e17820. Available: Scholar
  244. 244.
    Warf MB, Berglund JA. MBNL binds similar RNA structures in the CUG repeats of myotonic dystrophy and its pre-mRNA substrate cardiac troponin T. RNA. 2007;13:2238–51. Scholar
  245. 245.
    Kino Y, Mori D, Oma Y, Takeshita Y, Sasagawa N, Ishiura S. Muscleblind protein, MBNL1/EXP, binds specifically to CHHG repeats. Hum Mol Genet. 2004;13:495–507. Scholar
  246. 246.
    Du H, Cline MS, Osborne RJ, Tuttle DL, Clark TA, Donohue JP, et al. Aberrant alternative splicing and extracellular matrix gene expression in mouse models of myotonic dystrophy. Nat Struct Mol Biol. 2010;17:187–93. Scholar
  247. 247.
    Miller JW, Urbinati CR, Teng-Umnuay P, Stenberg MG, Byrne BJ, Thornton CA, et al. Recruitment of human muscleblind proteins to (CUG)(n) expansions associated with myotonic dystrophy. EMBO J. 2000;19:4439–48. Scholar
  248. 248.
    Konieczny P, Selma-Soriano E, Rapisarda AS, Fernandez-Costa JM, Perez-Alonso M, Artero R. Myotonic dystrophy: candidate small molecule therapeutics. Drug Discov Today. 2017.
  249. 249.
    Taneja KL, McCurrach M, Schalling M, Housman D, Singer RH. Foci of trinucleotide repeat transcripts in nuclei of myotonic dystrophy cells and tissues. J Cell Biol. 1995;128:995–1002. Available: Scholar
  250. 250.
    Liquori CL, Ricker K, Moseley ML, Jacobsen JF, Kress W, Naylor SL, et al. Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9. Science. 2001;293:864–7. Scholar
  251. 251.
    Lu X, Timchenko NA, Timchenko LT. Cardiac elav-type RNA-binding protein (ETR-3) binds to RNA CUG repeats expanded in myotonic dystrophy. Hum Mol Genet. 1999;8:53–60. Available: Scholar
  252. 252.
    Mizielinska S, Lashley T, Norona FE, Clayton EL, Ridler CE, Fratta P, et al. C9orf72 frontotemporal lobar degeneration is characterised by frequent neuronal sense and antisense RNA foci. Acta Neuropathol. 2013;126:845–57. Scholar
  253. 253.
    Vatovec S, Kovanda A, Rogelj B. Unconventional features of C9ORF72 expanded repeat in amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Neurobiol Aging. 2014;35:2421.e1–2421.e12. Scholar
  254. 254.
    Zu T, Gibbens B, Doty NS, Gomes-Pereira M, Huguet A, Stone MD, et al. Non-ATG-initiated translation directed by microsatellite expansions. Proc Natl Acad Sci U S A. 2011;108:260–5. Scholar
  255. 255.
    Kearse MG, Green KM, Krans A, Rodriguez CM, Linsalata AE, Goldstrohm AC, et al. CGG repeat-associated non-AUG translation utilizes a cap-dependent scanning mechanism of initiation to produce toxic proteins. Mol Cell. 2016;62:314–22. Scholar
  256. 256.
    Todd PK, Oh SY, Krans A, He F, Sellier C, Frazer M, et al. CGG repeat-associated translation mediates neurodegeneration in fragile X tremor ataxia syndrome. Neuron. 2013;78:440–55. Scholar
  257. 257.
    Bañez-Coronel M, Ayhan F, Tarabochia AD, Zu T, Perez BA, Tusi SK, et al. RAN translation in huntington disease. Neuron. 2015;88:667–77. Scholar
  258. 258.
    Zu T, Liu Y, Bañez-Coronel M, Reid T, Pletnikova O, Lewis J, 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:E4968–77. Scholar
  259. 259.
    Zu T, Cleary JD, Liu Y, Bañez-Coronel M, Bubenik JL, Ayhan F, et al. RAN translation regulated by muscleblind proteins in myotonic dystrophy type 2. Neuron. 2017;95:1292–1305.e5. Scholar
  260. 260.
    May S, Hornburg D, Schludi MH, Arzberger T, Rentzsch K, Schwenk BM, et al. C9orf72 FTLD/ALS-associated Gly-Ala dipeptide repeat proteins cause neuronal toxicity and Unc119 sequestration. Acta Neuropathol. 2014;128:485–503. Scholar
  261. 261.
    Tran H, Almeida S, Moore J, Gendron TF, Chalasani U, Lu Y, et al. Differential toxicity of nuclear RNA foci versus dipeptide repeat proteins in a Drosophila model of C9ORF72 FTD/ALS. Neuron. 2015;87:1207–14. Scholar
  262. 262.
    Kwon I, Xiang S, Kato M, Wu L, Theodoropoulos P, Wang T, et al. Poly-dipeptides encoded by the C9orf72 repeats bind nucleoli, impede RNA biogenesis, and kill cells. Science. 2014;345:1139–45. Scholar
  263. 263.
    Lee K-H, Zhang P, Kim HJ, Mitrea DM, Sarkar M, Freibaum BD, et al. C9orf72 dipeptide repeats impair the assembly, dynamics, and function of membrane-less organelles. Cell. 2016;167:774–788.e17. Scholar
  264. 264.
    Henras AK, Plisson-Chastang C, O’Donohue M-F, Chakraborty A, Gleizes P-E. An overview of pre-ribosomal RNA processing in eukaryotes. Wiley Interdiscip Rev RNA. 2015;6:225–42. Scholar
  265. 265.
    Staněk D, Přidalová-Hnilicová J, Novotný I, Huranová M, Blažíková M, Wen X, et al. Spliceosomal small nuclear ribonucleoprotein particles repeatedly cycle through Cajal bodies. Mol Biol Cell. 2008;19:2534–43. Scholar
  266. 266.
    Wen X, Tan W, Westergard T, Krishnamurthy K, Markandaiah SS, Shi Y, et al. Antisense proline-arginine RAN dipeptides linked to C9ORF72-ALS/FTD form toxic nuclear aggregates that initiate in vitro and in vivo neuronal death. Neuron. 2014;84:1213–25. Scholar
  267. 267.
    Masuda S, Das R, Cheng H, Hurt E, Dorman N, Reed R. Recruitment of the human TREX complex to mRNA during splicing. Genes Dev. 2005;19:1512–7. Scholar
  268. 268.
    Luo ML, Zhou Z, Magni K, Christoforides C, Rappsilber J, Mann M, et al. Pre-mRNA splicing and mRNA export linked by direct interactions between UAP56 and Aly. Nature. 2001;413:644–7. Scholar
  269. 269.
    Hautbergue GM, Hung M-L, Walsh MJ, Snijders APL, Chang C-T, Jones R, et al. UIF, a new mRNA export adaptor that works together with REF/ALY, requires FACT for recruitment to mRNA. Curr Biol. 2009;19:1918–24. Scholar
  270. 270.
    Viphakone N, Cumberbatch MG, Livingstone MJ, Heath PR, Dickman MJ, Catto JW, et al. Luzp4 defines a new mRNA export pathway in cancer cells. Nucleic Acids Res. 2015;43:2353–66. Scholar
  271. 271.
    Chang C-T, Hautbergue GM, Walsh MJ, Viphakone N, van Dijk TB, Philipsen S, et al. Chtop is a component of the dynamic TREX mRNA export complex. EMBO J. 2013;32:473–86. Scholar
  272. 272.
    Hautbergue GM, Hung M-L, Golovanov AP, Lian L-Y, Wilson SA. Mutually exclusive interactions drive handover of mRNA from export adaptors to TAP. Proc Natl Acad Sci U S A. 2008;105:5154–9. Scholar
  273. 273.
    Viphakone N, Hautbergue GM, Walsh M, Chang C-T, Holland A, Folco EG, et al. TREX exposes the RNA-binding domain of Nxf1 to enable mRNA export. Nat Commun. 2012;3:1006. Scholar
  274. 274.
    Stutz F, Bachi A, Doerks T, Braun IC, Séraphin B, Wilm M, et al. REF, an evolutionarily conserved family of hnRNP-like proteins, interacts with TAP/Mex67p and participates in mRNA nuclear export. RNA. 2000;6:638–50. Available: Scholar
  275. 275.
    Wickramasinghe VO, McMurtrie PIA, Mills AD, Takei Y, Penrhyn-Lowe S, Amagase Y, et al. mRNA export from mammalian cell nuclei is dependent on GANP. Curr Biol. 2010;20:25–31. Scholar
  276. 276.
    Bergeron D, Pal G, Beaulieu YB, Chabot B, Bachand F. Regulated intron retention and nuclear pre-mRNA decay contribute to PABPN1 autoregulation. Mol Cell Biol. 2015;35:2503–17. Scholar
  277. 277.
    Avendaño-Vázquez SE, Dhir A, Bembich S, Buratti E, Proudfoot N, Baralle FE. Autoregulation of TDP-43 mRNA levels involves interplay between transcription, splicing, and alternative polyA site selection. Genes Dev. 2012;26:1679–84. Scholar
  278. 278.
    Di Gregorio E, Bianchi FT, Schiavi A, Chiotto AMA, Rolando M, di Cantogno LV, et al. A de novo X; 8 translocation creates a PTK2-THOC2 gene fusion with THOC2 expression knockdown in a patient with psychomotor retardation and congenital cerebellar hypoplasia. J Med Genet. BMJ. 2013;50:543–51. Available: Scholar
  279. 279.
    Kumar R, Corbett MA, van Bon BWM, Woenig JA, Weir L, Douglas E, et al. THOC2 mutations implicate mRNA-export pathway in X-linked intellectual disability. Am J Hum Genet. 2015;97:302–10. Scholar
  280. 280.
    Beaulieu CL, Huang L, Innes AM, Akimenko M-A, Puffenberger EG, Schwartz C, et al. Intellectual disability associated with a homozygous missense mutation in THOC6. Orphanet J Rare Dis. 2013;8:62. Scholar
  281. 281.
    Kaneb HM, Folkmann AW, Belzil VV, Jao L-E, Leblond CS, Girard SL, et al. Deleterious mutations in the essential mRNA metabolism factor, hGle1, in amyotrophic lateral sclerosis. Hum Mol Genet. 2015;24:1363–73. Scholar
  282. 282.
    Nousiainen HO, Kestilä M, Pakkasjärvi N, Honkala H, Kuure S, Tallila J, et al. Mutations in mRNA export mediator GLE1 result in a fetal motoneuron disease. Nat Genet. 2008;40:155–7. Scholar
  283. 283.
    Folkmann AW, Noble KN, Cole CN, Wente SR. Dbp5, Gle1-IP6 and Nup159: a working model for mRNP export. Nucleus. 2011;2:540–8. Scholar
  284. 284.
    Murphy R, Watkins JL, Wente SR. GLE2, a Saccharomyces cerevisiae homologue of the Schizosaccharomyces pombe export factor RAE1, is required for nuclear pore complex structure and function. Mol Biol Cell. 1996;7:1921–37. Available: Scholar
  285. 285.
    Bharathi A, Ghosh A, Whalen WA, Yoon JH, Pu R, Dasso M, et al. The human RAE1 gene is a functional homologue of Schizosaccharomyces pombe rae1 gene involved in nuclear export of Poly(A)+ RNA. Gene. 1997;198:251–8. Available: Scholar
  286. 286.
    Freibaum BD, Lu Y, Lopez-Gonzalez R, Kim NC, Almeida S, Lee K-H, et al. GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport. Nature. 2015;525:129–33. Scholar
  287. 287.
    Jovičić A, Mertens J, Boeynaems S, Bogaert E, Chai N, Yamada SB, et al. Modifiers of C9orf72 dipeptide repeat toxicity connect nucleocytoplasmic transport defects to FTD/ALS. Nat Neurosci. 2015;18:1226–9. Scholar
  288. 288.
    Zhang K, Donnelly CJ, Haeusler AR, Grima JC, Machamer JB, Steinwald P, et al. The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature. 2015;525:56–61. Scholar
  289. 289.
    Garcia-Lopez A, Monferrer L, Garcia-Alcover I, Vicente-Crespo M, Alvarez-Abril MC, Artero RD. Genetic and chemical modifiers of a CUG toxicity model in Drosophila. PLoS One. 2008;3:e1595. Scholar
  290. 290.
    Sun X, Li PP, Zhu S, Cohen R, Marque LO, Ross CA, et al. Nuclear retention of full-length HTT RNA is mediated by splicing factors MBNL1 and U2AF65. Sci Rep. 2015;5:12521. Scholar
  291. 291.
    Grima JC, Daigle JG, Arbez N, Cunningham KC, Zhang K, Ochaba J, et al. Mutant Huntingtin disrupts the nuclear pore complex. Neuron. 2017;94:93–107.e6. Scholar
  292. 292.
    D’Angelo MA, Raices M, Panowski SH, Hetzer MW. Age-dependent deterioration of nuclear pore complexes causes a loss of nuclear integrity in postmitotic cells. Cell. 2009;136:284–95. Scholar
  293. 293.
    Mertens J, Paquola ACM, Ku M, Hatch E, Böhnke L, Ladjevardi S, et al. Directly reprogrammed human neurons retain aging-associated transcriptomic signatures and reveal age-related nucleocytoplasmic defects. Cell Stem Cell. 2015;17:705–18. Scholar
  294. 294.
    Shi KY, Mori E, Nizami ZF, Lin Y, Kato M, Xiang S, et al. Toxic PRn poly-dipeptides encoded by the C9orf72 repeat expansion block nuclear import and export. Proc Natl Acad Sci U S A. 2017;114:E1111–7. Scholar
  295. 295.
    Mizielinska S, Grönke S, Niccoli T, Ridler CE, Clayton EL, Devoy A, et al. C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins. Science. 2014;345:1192–4. Scholar
  296. 296.
    Eggens VR, Barth PG, Niermeijer J-MF, Berg JN, Darin N, Dixit A, et al. EXOSC3 mutations in pontocerebellar hypoplasia type 1: novel mutations and genotype-phenotype correlations. Orphanet J Rare Dis. 2014;9:23. Scholar
  297. 297.
    Rudnik-Schöneborn S, Senderek J, Jen JC, Houge G, Seeman P, Puchmajerová A, et al. Pontocerebellar hypoplasia type 1: clinical spectrum and relevance of EXOSC3 mutations. Neurology. 2013;80:438–46. Scholar
  298. 298.
    Zanni G, Scotton C, Passarelli C, Fang M, Barresi S, Dallapiccola B, et al. Exome sequencing in a family with intellectual disability, early onset spasticity, and cerebellar atrophy detects a novel mutation in EXOSC3. Neurogenetics. 2013;14:247–50. Scholar
  299. 299.
    Boczonadi V, Müller JS, Pyle A, Munkley J, Dor T, Quartararo J, et al. EXOSC8 mutations alter mRNA metabolism and cause hypomyelination with spinal muscular atrophy and cerebellar hypoplasia. Nat Commun. 2014;5:4287. Scholar
  300. 300.
    Pan Q, Shai O, Lee LJ, Frey BJ, Blencowe BJ. Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing. Nat Genet. 2008;40:1413–5. Scholar
  301. 301.
    Johnson MB, Kawasawa YI, Mason CE, Krsnik Z, Coppola G, Bogdanović D, et al. Functional and evolutionary insights into human brain development through global transcriptome analysis. Neuron. 2009;62:494–509. Scholar
  302. 302.
    Yeo G, Holste D, Kreiman G, Burge CB. Variation in alternative splicing across human tissues. Genome Biol. 2004;5:R74. Scholar
  303. 303.
    Faustino NA, Cooper TA. Pre-mRNA splicing and human disease. Genes Dev. 2003;17:419–37. Scholar
  304. 304.
    Sassi C, Capozzo R, Gibbs R, Crews C, Zecca C, Arcuti S, et al. A novel splice-acceptor site mutation in GRN (c. 709-2 A>T) causes frontotemporal dementia spectrum in a large family from Southern Italy. J Alzheimers Dis. 2016;53:475–85. Available: Scholar
  305. 305.
    Luzzi S, Colleoni L, Corbetta P, Baldinelli S, Fiori C, Girelli F, et al. Missense mutation in GRN gene affecting RNA splicing and plasma progranulin level in a family affected by frontotemporal lobar degeneration. Neurobiol Aging. 2017;54:214.e1–6. Scholar
  306. 306.
    Mukherjee O, Wang J, Gitcho M, Chakraverty S, Taylor-Reinwald L, Shears S, et al. Molecular characterization of novel progranulin (GRN) mutations in frontotemporal dementia. Hum Mutat. 2008;29:512–21. Scholar
  307. 307.
    Guven G, Lohmann E, Bras J, Gibbs JR, Gurvit H, Bilgic B, et al. Mutation frequency of the major frontotemporal dementia genes, MAPT, GRN and C9ORF72 in a Turkish cohort of dementia patients. PLoS One. 2016;11:e0162592. Scholar
  308. 308.
    Humphrey J, Emmett W, Fratta P, Isaacs AM, Plagnol V. Quantitative analysis of cryptic splicing associated with TDP-43 depletion. BMC Med Genet. 2017;10:38. Scholar
  309. 309.
    Tan Q, Yalamanchili HK, Park J, De Maio A, Lu H-C, Wan Y-W, et al. Extensive cryptic splicing upon loss of RBM17 and TDP43 in neurodegeneration models. Hum Mol Genet. 2016;25:5083–93. Scholar
  310. 310.
    Jeong YH, Ling JP, Lin SZ, Donde AN, Braunstein KE, Majounie E, et al. Tdp-43 cryptic exons are highly variable between cell types. Mol Neurodegener. 2017;12:13. Scholar
  311. 311.
    Shum EY, Jones SH, Shao A, Dumdie J, Krause MD, Chan W-K, et al. The antagonistic gene paralogs Upf3a and Upf3b govern nonsense-mediated RNA decay. Cell. 2016;165:382–95. Scholar
  312. 312.
    Barmada SJ, Ju S, Arjun A, Batarse A, Archbold HC, Peisach D, et al. Amelioration of toxicity in neuronal models of amyotrophic lateral sclerosis by hUPF1. Proc Natl Acad Sci U S A. 2015;112:7821–6. Scholar
  313. 313.
    Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, et al. Initial sequencing and analysis of the human genome. Nature. 2001;409:860–921. Scholar
  314. 314.
    Doucet AJ, Hulme AE, Sahinovic E, Kulpa DA, Moldovan JB, Kopera HC, et al. Characterization of LINE-1 ribonucleoprotein particles. PLoS Genet. 2010;6. Scholar
  315. 315.
    Cordaux R, Hedges DJ, Herke SW, Batzer MA. Estimating the retrotransposition rate of human Alu elements. Gene. 2006;373:134–7. Scholar
  316. 316.
    Maxwell PH, Burhans WC, Curcio MJ. Retrotransposition is associated with genome instability during chronological aging. Proc Natl Acad Sci U S A. 2011;108:20376–81. Scholar
  317. 317.
    Hua-Van A, Le Rouzic A, Boutin TS, Filée J, Capy P. The struggle for life of the genome’s selfish architects. Biol Direct. 2011;6:19. Scholar
  318. 318.
    Ramírez MA, Pericuesta E, Fernandez-Gonzalez R, Moreira P, Pintado B, Transcriptional G-AA. post-transcriptional regulation of retrotransposons IAP and MuERV-L affect pluripotency of mice ES cells. Reprod Biol Endocrinol. 2006;4:55. Scholar
  319. 319.
    Aguilera A. The connection between transcription and genomic instability. EMBO J. 2002;21:195–201. Available: Scholar
  320. 320.
    Gregersen LH, Schueler M, Munschauer M, Mastrobuoni G, Chen W, Kempa S, et al. MOV10 Is a 5′ to 3′ RNA helicase contributing to UPF1 mRNA target degradation by translocation along 3′ UTRs. Mol Cell. 2014;54:573–85. Scholar
  321. 321.
    Moldovan JB, Moran JV. The zinc-finger antiviral protein ZAP inhibits LINE and Alu retrotransposition. PLoS Genet. 2015;11:e1005121. Scholar
  322. 322.
    Saito K, Siomi MC. Small RNA-mediated quiescence of transposable elements in animals. Dev Cell. 2010;19:687–97. Scholar
  323. 323.
    De Cecco M, Criscione SW, Peterson AL, Neretti N, Sedivy JM, Kreiling JA. Transposable elements become active and mobile in the genomes of aging mammalian somatic tissues. Aging. 2013;5:867–83. Scholar
  324. 324.
    Li W, Prazak L, Chatterjee N, Grüninger S, Krug L, Theodorou D, et al. Activation of transposable elements during aging and neuronal decline in Drosophila. Nat Neurosci. 2013;16:529–31. Scholar
  325. 325.
    Douville R, Liu J, Rothstein J, Nath A. Identification of active loci of a human endogenous retrovirus in neurons of patients with amyotrophic lateral sclerosis. Ann Neurol. 2011;69:141–51. Scholar
  326. 326.
    Greenwood AD, Vincendeau M, Schmädicke A-C, Montag J, Seifarth W, Motzkus D. Bovine spongiform encephalopathy infection alters endogenous retrovirus expression in distinct brain regions of cynomolgus macaques (Macaca fascicularis). Mol Neurodegener. 2011;6:44. Scholar
  327. 327.
    Tan H, Qurashi A, Poidevin M, Nelson DL, Li H, Jin P. Retrotransposon activation contributes to fragile X premutation rCGG-mediated neurodegeneration. Hum Mol Genet. 2012;21:57–65. Scholar
  328. 328.
    Li W, Jin Y, Prazak L, Hammell M, Dubnau J. Transposable elements in TDP-43-mediated neurodegenerative disorders. PLoS One. 2012;7:e44099. Scholar
  329. 329.
    Krug L, Chatterjee N, Borges-Monroy R, Hearn S, Liao W-W, Morrill K, et al. Retrotransposon activation contributes to neurodegeneration in a Drosophila TDP-43 model of ALS. PLoS Genet. 2017;13:e1006635. Scholar
  330. 330.
    Subramanian RP, Wildschutte JH, Russo C, Coffin JM. Identification, characterization, and comparative genomic distribution of the HERV-K (HML-2) group of human endogenous retroviruses. Retrovirology. 2011;8:90. Scholar
  331. 331.
    Li W, Lee M-H, Henderson L, Tyagi R, Bachani M, Steiner J, et al. Human endogenous retrovirus-K contributes to motor neuron disease. Sci Transl Med. 2015;7:307ra153. Scholar
  332. 332.
    Carroll B, Hewitt G, Korolchuk VI. Autophagy and ageing: implications for age-related neurodegenerative diseases. Essays Biochem. 2013;55:119–31. Scholar
  333. 333.
    Romano AD, Serviddio G, de Matthaeis A, Bellanti F, Vendemiale G. Oxidative stress and aging. J Nephrol. 2010;23(Suppl 15):S29–36. Available: Scholar
  334. 334.
    Gensler HL, Bernstein H. DNA damage as the primary cause of aging. Q Rev Biol. 1981;56:279–303. Available: Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Neuroscience Graduate Program and Department of NeurologyUniversity of Michigan School of MedicineAnn ArborUSA

Personalised recommendations