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RNA Processing pp 263–296Cite as

RNA Granules and Diseases: A Case Study of Stress Granules in ALS and FTLD

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Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 907))

Abstract

RNA granules are microscopically visible cellular structures that aggregate by protein–protein and protein–RNA interactions. Using stress granules as an example, we discuss the principles of RNA granule formation, which rely on the multivalency of RNA and multi-domain proteins as well as low-affinity interactions between proteins with prion-like/low-complexity domains (e.g. FUS and TDP-43). We then explore how dysregulation of RNA granule formation is linked to neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), and discuss possible strategies for therapeutic intervention.

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References

  1. Höck J, Weinmann L, Ender C et al (2007) Proteomic and functional analysis of Argonaute-containing mRNA-protein complexes in human cells. EMBO Rep 8:1052–1060. doi:10.1038/sj.embor.7401088

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. La Rocca G, Olejniczak SH, González AJ et al (2015) In vivo, Argonaute-bound microRNAs exist predominantly in a reservoir of low molecular weight complexes not associated with mRNA. Proc Natl Acad Sci U S A 112:767–772. doi:10.1073/pnas.1424217112

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Bono F, Gehring NH (2011) Assembly, disassembly and recycling: the dynamics of exon junction complexes. RNA Biol 8:24–29

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Schoenberg DR, Maquat LE (2012) Regulation of cytoplasmic mRNA decay. Nat Rev Genet 13:246–259. doi:10.1038/nrg3160

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Anderson P, Kedersha NL (2009) RNA granules: post-transcriptional and epigenetic modulators of gene expression. Nat Rev Mol Cell Biol 10:430–436. doi:10.1038/nrm2694

    Article  CAS  PubMed  Google Scholar 

  6. Anderson P, Kedersha NL (2006) RNA granules. J Cell Biol 172:803–808. doi:10.1083/jcb.200512082

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Buchan JR, Parker R (2009) Eukaryotic stress granules: the ins and outs of translation. Mol Cell 36:932–941. doi:10.1016/j.molcel.2009.11.020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Spector DL (2006) SnapShot: cellular bodies. Cell 127:1071. doi:10.1016/j.cell.2006.11.026

    Article  PubMed  Google Scholar 

  9. Arrigo AP, Suhan JP, Welch WJ (1988) Dynamic changes in the structure and intracellular locale of the mammalian low-molecular-weight heat shock protein. Mol Cell Biol 8:5059–5071

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Collier NC, Heuser J, Levy MA, Schlesinger MJ (1988) Ultrastructural and biochemical analysis of the stress granule in chicken embryo fibroblasts. J Cell Biol 106:1131–1139

    Article  CAS  PubMed  Google Scholar 

  11. Collier NC, Schlesinger MJ (1986) The dynamic state of heat shock proteins in chicken embryo fibroblasts. J Cell Biol 103:1495–1507

    Article  CAS  PubMed  Google Scholar 

  12. Kedersha NL, Gupta M, Li W et al (1999) RNA-binding proteins TIA-1 and TIAR link the phosphorylation of eIF-2 alpha to the assembly of mammalian stress granules. J Cell Biol 147:1431–1442

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Buchan JR, Muhlrad D, Parker R (2008) P bodies promote stress granule assembly in Saccharomyces cerevisiae. J Cell Biol 183:441–455. doi:10.1083/jcb.200807043

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Farny NG, Kedersha NL, Silver PA (2009) Metazoan stress granule assembly is mediated by P-eIF2alpha-dependent and -independent mechanisms. RNA 15:1814–1821. doi:10.1261/rna.1684009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Grousl T, Ivanov P, Frydlova I et al (2009) Robust heat shock induces eIF2 -phosphorylation-independent assembly of stress granules containing eIF3 and 40S ribosomal subunits in budding yeast, Saccharomyces cerevisiae. J Cell Sci 122:2078–2088. doi:10.1242/jcs.045104

    Article  CAS  PubMed  Google Scholar 

  16. Hoyle NP, Castelli LM, Campbell SG et al (2007) Stress-dependent relocalization of translationally primed mRNPs to cytoplasmic granules that are kinetically and spatially distinct from P-bodies. J Cell Biol 179:65–74. doi:10.1083/jcb.200707010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Souquere S, Mollet S, Kress M et al (2009) Unravelling the ultrastructure of stress granules and associated P-bodies in human cells. J Cell Sci 122:3619–3626. doi:10.1242/jcs.054437

    Article  CAS  PubMed  Google Scholar 

  18. Anderson P, Kedersha NL (2008) Stress granules: the Tao of RNA triage. Trends Biochem Sci 33:141–150. doi:10.1016/j.tibs.2007.12.003

    Article  CAS  PubMed  Google Scholar 

  19. Kedersha NL, Anderson P (2007) Mammalian stress granules and processing bodies. Methods Enzymol 431:61–81. doi:10.1016/S0076-6879(07)31005-7

    Article  CAS  PubMed  Google Scholar 

  20. Moeller BJ, Cao Y, Li CY, Dewhirst MW (2004) Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors: role of reoxygenation, free radicals, and stress granules. Cancer Cell 5:429–441

    Article  CAS  PubMed  Google Scholar 

  21. White JP, Lloyd RE (2012) Regulation of stress granules in virus systems. Trends Microbiol 20:175–183. doi:10.1016/j.tim.2012.02.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Warner JR, Rich A, Hall CE (1962) Electron microscope studies of ribosomal clusters synthesizing hemoglobin. Science 138:1399–1403. doi:10.1126/science.138.3548.1399

    Article  CAS  PubMed  Google Scholar 

  23. Mokas S, Mills JR, Garreau C et al (2009) Uncoupling stress granule assembly and translation initiation inhibition. Mol Biol Cell 20:2673–2683. doi:10.1091/mbc.E08-10-1061

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Baguet A, Degot S, Cougot N et al (2007) The exon-junction-complex-component metastatic lymph node 51 functions in stress-granule assembly. J Cell Sci 120:2774–2784. doi:10.1242/jcs.009225

    Article  CAS  PubMed  Google Scholar 

  25. Kedersha NL, Stoecklin G, Ayodele M et al (2005) Stress granules and processing bodies are dynamically linked sites of mRNP remodeling. J Cell Biol 169:871–884. doi:10.1083/jcb.200502088

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Mazroui R, Huot M-E, Tremblay S et al (2002) Trapping of messenger RNA by Fragile X Mental Retardation protein into cytoplasmic granules induces translation repression. Hum Mol Genet 11:3007–3017

    Article  CAS  PubMed  Google Scholar 

  27. Wilczynska A, Aigueperse C, Kress M et al (2005) The translational regulator CPEB1 provides a link between dcp1 bodies and stress granules. J Cell Sci 118:981–992. doi:10.1242/jcs.01692

    Article  CAS  PubMed  Google Scholar 

  28. Kedersha NL, Ivanov P, Anderson P (2013) Stress granules and cell signaling: more than just a passing phase? Trends Biochem Sci. doi:10.1016/j.tibs.2013.07.004

    PubMed  PubMed Central  Google Scholar 

  29. Piotrowska J, Hansen SJ, Park N et al (2010) Stable formation of compositionally unique stress granules in virus-infected cells. J Virol 84:3654–3665. doi:10.1128/JVI.01320-09

    Article  CAS  PubMed  Google Scholar 

  30. Buchan JR, Yoon J-H, Parker R (2011) Stress-specific composition, assembly and kinetics of stress granules in saccharomyces cerevisiae. J Cell Sci 124:228–239. doi:10.1242/jcs.078444

    Article  CAS  PubMed  Google Scholar 

  31. Stoecklin G, Stubbs T, Kedersha NL et al (2004) MK2-induced tristetraprolin:14-3-3 complexes prevent stress granule association and ARE-mRNA decay. EMBO J 23:1313–1324. doi:10.1038/sj.emboj.7600163

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Gilks N, Kedersha NL, Ayodele M et al (2004) Stress granule assembly is mediated by prion-like aggregation of TIA-1. Mol Biol Cell 15:5383–5398. doi:10.1091/mbc.E04-08-0715

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Tanaka T, Ohashi S, Kobayashi S (2014) Roles of YB-1 under arsenite-induced stress: translational activation of HSP70 mRNA and control of the number of stress granules. Biochim Biophys Acta 1840:985–992. doi:10.1016/j.bbagen.2013.11.002

    Article  CAS  PubMed  Google Scholar 

  34. Mollet S, Cougot N, Wilczynska A et al (2008) Translationally repressed mRNA transiently cycles through stress granules during stress. Mol Biol Cell 19:4469–4479. doi:10.1091/mbc.E08-05-0499

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Zhang J, Okabe K, Tani T, Funatsu T (2011) Dynamic association-dissociation and harboring of endogenous mRNAs in stress granules. J Cell Sci 124:4087–4095. doi:10.1242/jcs.090951

    Article  CAS  PubMed  Google Scholar 

  36. Zhang T, Mullane PC, Periz G, Wang J (2011) TDP-43 neurotoxicity and protein aggregation modulated by heat shock factor and insulin/IGF-1 signaling. Hum Mol Genet 20:1952–1965

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kedersha NL, Anderson P (2002) Stress granules: sites of mRNA triage that regulate mRNA stability and translatability. Biochem Soc Trans 30:963–969

    Article  CAS  PubMed  Google Scholar 

  38. Kedersha NL, Cho MR, Li W et al (2000) Dynamic shuttling of TIA-1 accompanies the recruitment of mRNA to mammalian stress granules. J Cell Biol 151:1257–1268

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Hilliker A, Gao Z, Jankowsky E, Parker R (2011) The DEAD-box protein Ded1 modulates translation by the formation and resolution of an eIF4F-mRNA complex. Mol Cell 43:962–972. doi:10.1016/j.molcel.2011.08.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Shih J-W, Tsai T-Y, Chao C-H, Wu Lee Y-H (2008) Candidate tumor suppressor DDX3 RNA helicase specifically represses cap-dependent translation by acting as an eIF4E inhibitory protein. Oncogene 27:700–714. doi:10.1038/sj.onc.1210687

    Article  CAS  PubMed  Google Scholar 

  41. Arimoto K, Fukuda H, Imajoh-Ohmi S et al (2008) Formation of stress granules inhibits apoptosis by suppressing stress-responsive MAPK pathways. Nat Cell Biol 10:1324–1332. doi:10.1038/ncb1791

    Article  CAS  PubMed  Google Scholar 

  42. Eisinger-Mathason TSK, Andrade J, Groehler AL et al (2008) Codependent functions of RSK2 and the apoptosis-promoting factor TIA-1 in stress granule assembly and cell survival. Mol Cell 31:722–736. doi:10.1016/j.molcel.2008.06.025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Gareau C, Fournier M-J, Filion C et al (2011) p21(WAF1/CIP1) upregulation through the stress granule-associated protein CUGBP1 confers resistance to bortezomib-mediated apoptosis. PLoS One 6, e20254. doi:10.1371/journal.pone.0020254

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Thedieck K, Holzwarth B, Prentzell MT et al (2013) Inhibition of mTORC1 by astrin and stress granules prevents apoptosis in cancer cells. Cell 154:859–874. doi:10.1016/j.cell.2013.07.031

    Article  CAS  PubMed  Google Scholar 

  45. Kim WJ, Back SH, Kim V et al (2005) Sequestration of TRAF2 into stress granules interrupts tumor necrosis factor signaling under stress conditions. Mol Cell Biol 25:2450–2462. doi:10.1128/MCB.25.6.2450-2462.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Tsai N-P, Wei L-N (2010) RhoA/ROCK1 signaling regulates stress granule formation and apoptosis. Cell Signal 22:668–675. doi:10.1016/j.cellsig.2009.12.001

    Article  CAS  PubMed  Google Scholar 

  47. Li W, Simarro M, Kedersha NL, Anderson P (2004) FAST is a survival protein that senses mitochondrial stress and modulates TIA-1-regulated changes in protein expression. Mol Cell Biol 24:10718–10732. doi:10.1128/MCB.24.24.10718-10732.2004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Kwon S, Zhang Y, Matthias P (2007) The deacetylase HDAC6 is a novel critical component of stress granules involved in the stress response. Genes Dev 21:3381–3394. doi:10.1101/gad.461107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Fournier M-J, Coudert L, Mellaoui S et al (2013) Inactivation of the mTORC1-eukaryotic translation initiation factor 4E pathway alters stress granule formation. Mol Cell Biol 33:2285–2301. doi:10.1128/MCB.01517-12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Hofmann S, Cherkasova V, Bankhead P et al (2012) Translation suppression promotes stress granule formation and cell survival in response to cold shock. Mol Biol Cell 23:3786–3800. doi:10.1091/mbc.E12-04-0296

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Wippich F, Bodenmiller B, Trajkovska MG et al (2013) Dual specificity kinase DYRK3 couples stress granule condensation/dissolution to mTORC1 signaling. Cell 152:791–805. doi:10.1016/j.cell.2013.01.033

    Article  CAS  PubMed  Google Scholar 

  52. Fournier M-J, Gareau C, Mazroui R (2010) The chemotherapeutic agent bortezomib induces the formation of stress granules. Cancer Cell Int 10:12. doi:10.1186/1475-2867-10-12

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Li YR, King OD, Shorter J, Gitler AD (2013) Stress granules as crucibles of ALS pathogenesis. J Cell Biol 201:361–372. doi:10.1083/jcb.201302044

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Onomoto K, Yoneyama M, Fung G et al (2014) Antiviral innate immunity and stress granule responses. Trends Immunol. doi:10.1016/j.it.2014.07.006

    PubMed  Google Scholar 

  55. Banjade S, Rosen MK (2014) Phase transitions of multivalent proteins can promote clustering of membrane receptors. Elife. doi:10.7554/eLife.04123

    PubMed  PubMed Central  Google Scholar 

  56. Li P, Banjade S, Cheng H-C et al (2012) Phase transitions in the assembly of multivalent signalling proteins. Nature 483:336–340. doi:10.1038/nature10879

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Brangwynne CP (2013) Phase transitions and size scaling of membrane-less organelles. J Cell Biol 203:875–881. doi:10.1083/jcb.201308087

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Hyman AA, Simons K (2012) Cell biology. Beyond oil and water—phase transitions in cells. Science 337:1047–1049. doi:10.1126/science.1223728

    Article  CAS  PubMed  Google Scholar 

  59. Weber SC, Brangwynne CP (2012) Getting RNA and protein in phase. Cell 149:1188–1191. doi:10.1016/j.cell.2012.05.022

    Article  CAS  PubMed  Google Scholar 

  60. Kato M, Han TW, Xie S et al (2012) Cell-free formation of RNA granules: low complexity sequence domains form dynamic fibers within hydrogels. Cell 149:753–767. doi:10.1016/j.cell.2012.04.017

    Article  CAS  PubMed  Google Scholar 

  61. Schwartz JC, Wang X, Podell ER, Cech TR (2013) RNA seeds higher-order assembly of FUS protein. Cell Rep 5:918–925. doi:10.1016/j.celrep.2013.11.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Hyman AA, Weber CA, Jülicher F (2014) Liquid-liquid phase separation in biology. Annu Rev Cell Dev Biol 30:39–58. doi:10.1146/annurev-cellbio-100913-013325

    Article  CAS  PubMed  Google Scholar 

  63. Shevtsov SP, Dundr M (2011) Nucleation of nuclear bodies by RNA. Nat Cell Biol 13:167–173. doi:10.1038/ncb2157

    Article  CAS  PubMed  Google Scholar 

  64. Teixeira D, Sheth U, Valencia-Sanchez MA et al (2005) Processing bodies require RNA for assembly and contain nontranslating mRNAs. RNA 11:371–382. doi:10.1261/rna.7258505

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Leung AKL (2014) Poly(ADP-ribose): an organizer of cellular architecture. J Cell Biol 205:613–619. doi:10.1083/jcb.201402114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Leung AKL, Vyas S, Rood JE et al (2011) Poly(ADP-ribose) regulates stress responses and microRNA activity in the cytoplasm. Mol Cell 42:489–499. doi:10.1016/j.molcel.2011.04.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Shorter J, Lindquist S (2005) Prions as adaptive conduits of memory and inheritance. Nat Rev Genet 6:435–450. doi:10.1038/nrg1616

    Article  CAS  PubMed  Google Scholar 

  68. King OD, Gitler AD, Shorter J (2012) The tip of the iceberg: RNA-binding proteins with prion-like domains in neurodegenerative disease. Brain Res 1462:61–80. doi:10.1016/j.brainres.2012.01.016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Alberti S, Halfmann R, King O et al (2009) A systematic survey identifies prions and illuminates sequence features of prionogenic proteins. Cell 137:146–158. doi:10.1016/j.cell.2009.02.044

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Couthouis J, Hart MP, Shorter J et al (2011) A yeast functional screen predicts new candidate ALS disease genes. Proc Natl Acad Sci U S A 108:20881–20890. doi:10.1073/pnas.1109434108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Han TW, Kato M, Xie S et al (2012) Cell-free formation of RNA granules: bound RNAs identify features and components of cellular assemblies. Cell 149:768–779. doi:10.1016/j.cell.2012.04.016

    Article  CAS  PubMed  Google Scholar 

  72. Perutz MF, Johnson T, Suzuki M, Finch JT (1994) Glutamine repeats as polar zippers: their possible role in inherited neurodegenerative diseases. Proc Natl Acad Sci U S A 91:5355–5358

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Tourrière H, Chebli K, Zekri L et al (2003) The RasGAP-associated endoribonuclease G3BP assembles stress granules. J Cell Biol 160:823–831. doi:10.1083/jcb.200212128

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Glover JR, Lindquist S (1998) Hsp104, Hsp70, and Hsp40: a novel chaperone system that rescues previously aggregated proteins. Cell 94:73–82

    Article  CAS  PubMed  Google Scholar 

  75. Li X, Rayman JB, Kandel ER, Derkatch IL (2014) Functional role of Tia1/Pub1 and Sup35 prion domains: directing protein synthesis machinery to the tubulin cytoskeleton. Mol Cell. doi:10.1016/j.molcel.2014.05.027

    Google Scholar 

  76. Boyault C, Zhang Y, Fritah S et al (2007) HDAC6 controls major cell response pathways to cytotoxic accumulation of protein aggregates. Genes Dev 21:2172–2181. doi:10.1101/gad.436407

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Rikhvanov EG, Romanova NV, Chernoff YO (2007) Chaperone effects on prion and nonprion aggregates. Prion 1:217–222

    Article  PubMed  PubMed Central  Google Scholar 

  78. Guil S, Long JC, Cáceres JF (2006) hnRNP A1 relocalization to the stress granules reflects a role in the stress response. Mol Cell Biol 26:5744–5758. doi:10.1128/MCB.00224-06

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Schmidlin M, Lu M, Leuenberger SA et al (2004) The ARE-dependent mRNA-destabilizing activity of BRF1 is regulated by protein kinase B. EMBO J 23:4760–4769. doi:10.1038/sj.emboj.7600477

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Yoon J-H, Abdelmohsen K, Srikantan S et al (2013) Tyrosine phosphorylation of HuR by JAK3 triggers dissociation and degradation of HuR target mRNAs. Nucleic Acids Res. doi:10.1093/nar/gkt903

    Google Scholar 

  81. Hottiger MO, Hassa PO, Lüscher B et al (2010) Toward a unified nomenclature for mammalian ADP-ribosyltransferases. Trends Biochem Sci. doi:10.1016/j.tibs.2009.12.003

    PubMed  Google Scholar 

  82. van der Lee R, Buljan M, Lang B et al (2014) Classification of intrinsically disordered regions and proteins. Chem Rev 114:6589–6631. doi:10.1021/cr400525m

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Rowland LP, Shneider NA (2001) Amyotrophic lateral sclerosis. N Engl J Med 344:1688–1700. doi:10.1056/NEJM200105313442207

    Article  CAS  PubMed  Google Scholar 

  84. Rabinovici GD, Miller BL (2010) Frontotemporal lobar degeneration: epidemiology, pathophysiology, diagnosis and management. CNS Drugs 24:375–398. doi:10.2165/11533100-000000000-00000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Ling S-C, Polymenidou M, Cleveland DW (2013) Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis. Neuron 79:416–438. doi:10.1016/j.neuron.2013.07.033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Robberecht W, Philips T (2013) The changing scene of amyotrophic lateral sclerosis. Nat Rev Neurosci 14:248–264. doi:10.1038/nrn3430

    Article  CAS  PubMed  Google Scholar 

  87. Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, Bruce J, Schuck T, Grossman M, Clark CM, McCluskey LF, Miller BL, Masliah E, Mackenzie IR, Feldman H, Feiden W, Kretzschmar HA, Trojanowski JQ, Lee VM (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314(5796):130–133

    Article  CAS  PubMed  Google Scholar 

  88. Tollervey JR, Curk T, Rogelj B et al (2011) Characterizing the RNA targets and position-dependent splicing regulation by TDP-43. Nat Neurosci 14:452–458. doi:10.1038/nn.2778

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Lagier-Tourenne C, Polymenidou M, Hutt KR et al (2012) Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs. Nat Neurosci 15:1488–1497. doi:10.1038/nn.3230

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. McDonald KK, Aulas A, Destroismaisons L et al (2011) TAR DNA-binding protein 43 (TDP-43) regulates stress granule dynamics via differential regulation of G3BP and TIA-1. Hum Mol Genet 20:1400–1410. doi:10.1093/hmg/ddr021

    Article  CAS  PubMed  Google Scholar 

  91. Liu-Yesucevitz L, Bilgutay A, Zhang Y-J et al (2010) Tar DNA binding protein-43 (TDP-43) associates with stress granules: analysis of cultured cells and pathological brain tissue. PLoS One 5, e13250. doi:10.1371/journal.pone.0013250

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Dewey CM, Cenik B, Sephton CF et al (2011) TDP-43 is directed to stress granules by sorbitol, a novel physiological osmotic and oxidative stressor. Mol Cell Biol 31:1098–1108. doi:10.1128/MCB.01279-10

    Article  CAS  PubMed  Google Scholar 

  93. Bentmann E, Neumann M, Tahirovic S et al (2012) Requirements for stress granule recruitment of fused in sarcoma (FUS) and TAR DNA-binding protein of 43 kDa (TDP-43). J Biol Chem 287:23079–23094. doi:10.1074/jbc.M111.328757

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Liu-Yesucevitz L, Lin AY, Ebata A et al (2014) ALS-linked mutations enlarge TDP-43-enriched neuronal RNA granules in the dendritic arbor. J Neurosci 34:4167–4174. doi:10.1523/JNEUROSCI.2350-13.2014

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Chiò A, Calvo A, Mazzini L et al (2012) Extensive genetics of ALS: a population-based study in Italy. Neurology 79:1983–1989. doi:10.1212/WNL.0b013e3182735d36

    Article  PubMed  PubMed Central  Google Scholar 

  96. Aulas A, Stabile S, Vande Velde C (2012) Endogenous TDP-43, but not FUS, contributes to stress granule assembly via G3BP. Mol Neurodegener 7:54. doi:10.1186/1750-1326-7-54

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Aulas A, Caron G, Gkogkas CG et al (2015) G3BP1 promotes stress-induced RNA granule interactions to preserve polyadenylated mRNA. J Cell Biol 209:73–84. doi:10.1083/jcb.201408092

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Iko Y, Kodama TS, Kasai N et al (2004) Domain architectures and characterization of an RNA-binding protein, TLS. J Biol Chem 279:44834–44840. doi:10.1074/jbc.M408552200

    Article  CAS  PubMed  Google Scholar 

  99. Dormann D, Rodde R, Edbauer D et al (2010) ALS-associated fused in sarcoma (FUS) mutations disrupt Transportin-mediated nuclear import. EMBO J 29:2841–2857. doi:10.1038/emboj.2010.143

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Gal J, Zhang J, Kwinter DM et al (2011) Nuclear localization sequence of FUS and induction of stress granules by ALS mutants. Neurobiol Aging 32:2323.e27–2323.e40. doi:10.1016/j.neurobiolaging.2010.06.010

    Article  CAS  Google Scholar 

  101. Bosco DA, Lemay N, Ko HK et al (2010) Mutant FUS proteins that cause amyotrophic lateral sclerosis incorporate into stress granules. Hum Mol Genet 19:4160–4175. doi:10.1093/hmg/ddq335

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Ito D, Suzuki N (2011) Conjoint pathologic cascades mediated by ALS/FTLD-U linked RNA-binding proteins TDP-43 and FUS. Neurology 77(17):1636–1643

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Vance C, Scotter EL, Nishimura AL et al (2013) ALS mutant FUS disrupts nuclear localization and sequesters wild-type FUS within cytoplasmic stress granules. Hum Mol Genet 22:2676–2688. doi:10.1093/hmg/ddt117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Daigle JG, Lanson NA, Smith RB et al (2013) RNA-binding ability of FUS regulates neurodegeneration, cytoplasmic mislocalization and incorporation into stress granules associated with FUS carrying ALS-linked mutations. Hum Mol Genet 22:1193–1205. doi:10.1093/hmg/dds526

    Article  CAS  PubMed  Google Scholar 

  105. Kino Y, Washizu C, Aquilanti E et al (2011) Intracellular localization and splicing regulation of FUS/TLS are variably affected by amyotrophic lateral sclerosis-linked mutations. Nucleic Acids Res 39:2781–2798. doi:10.1093/nar/gkq1162

    Article  CAS  PubMed  Google Scholar 

  106. Andersson MK, Ståhlberg A, Arvidsson Y et al (2008) The multifunctional FUS, EWS and TAF15 proto-oncoproteins show cell type-specific expression patterns and involvement in cell spreading and stress response. BMC Cell Biol 9:37. doi:10.1186/1471-2121-9-37

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Blechingberg J, Luo Y, Bolund L et al (2012) Gene expression responses to FUS, EWS, and TAF15 reduction and stress granule sequestration analyses identifies FET-protein non-redundant functions. PLoS One 7, e46251. doi:10.1371/journal.pone.0046251

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Sama RRK, Ward CL, Kaushansky LJ et al (2013) FUS/TLS assembles into stress granules and is a prosurvival factor during hyperosmolar stress. J Cell Physiol 228:2222–2231. doi:10.1002/jcp.24395

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Zhang ZC, Chook YM (2012) 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 109:12017–12021. doi:10.1073/pnas.1207247109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Dormann D, Madl T, Valori CF et al (2012) Arginine methylation next to the PY-NLS modulates Transportin binding and nuclear import of FUS. EMBO J 31:4258–4275. doi:10.1038/emboj.2012.261

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Johnson BS, Snead D, Lee JJ et al (2009) TDP-43 is intrinsically aggregation-prone, and amyotrophic lateral sclerosis-linked mutations accelerate aggregation and increase toxicity. J Biol Chem 284:20329–20339. doi:10.1074/jbc.M109.010264

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Cushman M, Johnson BS, King OD et al (2010) Prion-like disorders: blurring the divide between transmissibility and infectivity. J Cell Sci 123:1191–1201. doi:10.1242/jcs.051672

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Fushimi K, Long C, Jayaram N et al (2011) Expression of human FUS/TLS in yeast leads to protein aggregation and cytotoxicity, recapitulating key features of FUS proteinopathy. Protein Cell 2:141–149. doi:10.1007/s13238-011-1014-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Sun Z, Diaz Z, Fang X et al (2011) Molecular determinants and genetic modifiers of aggregation and toxicity for the ALS disease protein FUS/TLS. PLoS Biol 9, e1000614. doi:10.1371/journal.pbio.1000614

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Barmada SJ, Skibinski G, Korb E et al (2010) Cytoplasmic mislocalization of TDP-43 is toxic to neurons and enhanced by a mutation associated with familial amyotrophic lateral sclerosis. J Neurosci 30:639–649. doi:10.1523/JNEUROSCI.4988-09.2010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Ling S-C, Albuquerque CP, Han JS et al (2010) ALS-associated mutations in TDP-43 increase its stability and promote TDP-43 complexes with FUS/TLS. Proc Natl Acad Sci U S A 107:13318–13323. doi:10.1073/pnas.1008227107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Johnson BS, McCaffery JM, Lindquist S, Gitler AD (2008) A yeast TDP-43 proteinopathy model: exploring the molecular determinants of TDP-43 aggregation and cellular toxicity. Proc Natl Acad Sci U S A 105:6439–6444. doi:10.1073/pnas.0802082105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Kabashi E, Lin L, Tradewell ML et al (2010) Gain and loss of function of ALS-related mutations of TARDBP (TDP-43) cause motor deficits in vivo. Hum Mol Genet 19:671–683. doi:10.1093/hmg/ddp534

    Article  CAS  PubMed  Google Scholar 

  119. Lanson NA, Maltare A, King H et al (2011) A Drosophila model of FUS-related neurodegeneration reveals genetic interaction between FUS and TDP-43. Hum Mol Genet 20:2510–2523. doi:10.1093/hmg/ddr150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Polymenidou M, Cleveland DW (2011) The seeds of neurodegeneration: prion-like spreading in ALS. Cell 147:498–508. doi:10.1016/j.cell.2011.10.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Meyerowitz J, Parker SJ, Vella LJ et al (2011) C-Jun N-terminal kinase controls TDP-43 accumulation in stress granules induced by oxidative stress. Mol Neurodegener 6:57. doi:10.1186/1750-1326-6-57

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Parker SJ, Meyerowitz J, James JL et al (2012) Endogenous TDP-43 localized to stress granules can subsequently form protein aggregates. Neurochem Int 60:415–424. doi:10.1016/j.neuint.2012.01.019

    Article  CAS  PubMed  Google Scholar 

  123. Kim SH, Shanware NP, Bowler MJ, Tibbetts RS (2010) Amyotrophic lateral sclerosis-associated proteins TDP-43 and FUS/TLS function in a common biochemical complex to co-regulate HDAC6 mRNA. J Biol Chem 285:34097–34105. doi:10.1074/jbc.M110.154831

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Polymenidou M, Lagier-Tourenne C, Hutt KR et al (2011) Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43. Nat Neurosci 14:459–468. doi:10.1038/nn.2779

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Arnold ES, Ling S-C, Huelga SC et al (2013) ALS-linked TDP-43 mutations produce aberrant RNA splicing and adult-onset motor neuron disease without aggregation or loss of nuclear TDP-43. Proc Natl Acad Sci U S A 110:E736–E745. doi:10.1073/pnas.1222809110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Igaz LM, Kwong LK, Lee EB et al (2011) Dysregulation of the ALS-associated gene TDP-43 leads to neuronal death and degeneration in mice. J Clin Invest 121:726–738. doi:10.1172/JCI44867

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Hicks GG, Singh N, Nashabi A et al (2000) Fus deficiency in mice results in defective B-lymphocyte development and activation, high levels of chromosomal instability and perinatal death. Nat Genet 24:175–179. doi:10.1038/72842

    Article  CAS  PubMed  Google Scholar 

  128. Sasayama H, Shimamura M, Tokuda T et al (2012) Knockdown of the Drosophila fused in sarcoma (FUS) homologue causes deficient locomotive behavior and shortening of motoneuron terminal branches. PLoS One 7, e39483. doi:10.1371/journal.pone.0039483

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Chen Y, Yang M, Deng J et al (2011) Expression of human FUS protein in Drosophila leads to progressive neurodegeneration. Protein Cell 2:477–486. doi:10.1007/s13238-011-1065-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Huang C, Zhou H, Tong J et al (2011) FUS transgenic rats develop the phenotypes of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. PLoS Genet 7, e1002011. doi:10.1371/journal.pgen.1002011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Qiu H, Lee S, Shang Y et al (2014) ALS-associated mutation FUS-R521C causes DNA damage and RNA splicing defects. J Clin Invest 124:981–999. doi:10.1172/JCI72723

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Yasuda K, Zhang H, Loiselle D et al (2013) The RNA-binding protein Fus directs translation of localized mRNAs in APC-RNP granules. J Cell Biol 203:737–746. doi:10.1083/jcb.201306058

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Barber SC, Shaw PJ (2010) Oxidative stress in ALS: key role in motor neuron injury and therapeutic target. Free Radic Biol Med 48:629–641. doi:10.1016/j.freeradbiomed.2009.11.018

    Article  CAS  PubMed  Google Scholar 

  134. Beal MF (2002) Oxidatively modified proteins in aging and disease. Free Radic Biol Med 32:797–803

    Article  CAS  PubMed  Google Scholar 

  135. Carrì MT, Valle C, Bozzo F, Cozzolino M (2015) Oxidative stress and mitochondrial damage: importance in non-SOD1 ALS. Front Cell Neurosci 9:41. doi:10.3389/fncel.2015.00041

    PubMed  PubMed Central  Google Scholar 

  136. Shaw PJ, Ince PG, Falkous G, Mantle D (1995) Oxidative damage to protein in sporadic motor neuron disease spinal cord. Ann Neurol 38:691–695. doi:10.1002/ana.410380424

    Article  CAS  PubMed  Google Scholar 

  137. Bogdanov M, Brown RH, Matson W et al (2000) Increased oxidative damage to DNA in ALS patients. Free Radic Biol Med 29:652–658

    Article  CAS  PubMed  Google Scholar 

  138. Ferrante RJ, Browne SE, Shinobu LA et al (1997) Evidence of increased oxidative damage in both sporadic and familial amyotrophic lateral sclerosis. J Neurochem 69:2064–2074

    Article  CAS  PubMed  Google Scholar 

  139. Ihara Y, Nobukuni K, Takata H, Hayabara T (2005) Oxidative stress and metal content in blood and cerebrospinal fluid of amyotrophic lateral sclerosis patients with and without a Cu, Zn-superoxide dismutase mutation. Neurol Res 27:105–108. doi:10.1179/016164105X18430

    Article  CAS  PubMed  Google Scholar 

  140. Shibata N, Nagai R, Uchida K et al (2001) Morphological evidence for lipid peroxidation and protein glycoxidation in spinal cords from sporadic amyotrophic lateral sclerosis patients. Brain Res 917:97–104

    Article  CAS  PubMed  Google Scholar 

  141. Hirano M et al. (2015) VCP gene analyses in Japanese patients with sporadic amyotrophic lateral sclerosis identify a new mutation. Neurobiol. Aging 36: 1604.e1–6

    Google Scholar 

  142. Weiduschat N et al (2014) Motor cortex glutathione deficit in ALS measured in vivo with the J-editing technique. Neurosci Lett 570:102–107

    Article  CAS  PubMed  Google Scholar 

  143. Iguchi Y, Katsuno M, Takagi S et al (2012) Oxidative stress induced by glutathione depletion reproduces pathological modifications of TDP-43 linked to TDP-43 proteinopathies. Neurobiol Dis 45:862–870. doi:10.1016/j.nbd.2011.12.002

    Article  CAS  PubMed  Google Scholar 

  144. Kim H-J, Raphael AR, LaDow ES et al (2013) Therapeutic modulation of eIF2α phosphorylation rescues TDP-43 toxicity in amyotrophic lateral sclerosis disease models. Nat Genet. doi:10.1038/ng.2853

    Google Scholar 

  145. Kim HJ, Kim NC, Wang Y-D et al (2013) Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature 495:467–473. doi:10.1038/nature11922

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Couthouis J, Hart MP, Erion R et al (2012) Evaluating the role of the FUS/TLS-related gene EWSR1 in amyotrophic lateral sclerosis. Hum Mol Genet 21:2899–2911. doi:10.1093/hmg/dds116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Mackenzie IRA, Neumann M (2012) FET proteins in frontotemporal dementia and amyotrophic lateral sclerosis. Brain Res 1462:40–43. doi:10.1016/j.brainres.2011.12.010

    Article  CAS  PubMed  Google Scholar 

  148. Ash PEA, Vanderweyde TE, Youmans KL et al (2014) Pathological stress granules in Alzheimer’s disease. Brain Res 1584:52–58. doi:10.1016/j.brainres.2014.05.052

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Banks GT, Kuta A, Isaacs AM, Fisher EMC (2008) TDP-43 is a culprit in human neurodegeneration, and not just an innocent bystander. Mamm Genome 19:299–305. doi:10.1007/s00335-008-9117-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Vanderweyde T, Yu H, Varnum M et al (2012) Contrasting pathology of the stress granule proteins TIA-1 and G3BP in tauopathies. J Neurosci 32:8270–8283. doi:10.1523/JNEUROSCI.1592-12.2012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Sidrauski C, McGeachy AM, Ingolia NT, Walter P (2015) The small molecule ISRIB reverses the effects of eIF2α phosphorylation on translation and stress granule assembly. Elife. doi:10.7554/eLife.05033

    Google Scholar 

  152. Gambetta MC, Müller J (2014) O-GlcNAcylation prevents aggregation of the Polycomb group repressor Polyhomeotic. Dev Cell 31:629–639. doi:10.1016/j.devcel.2014.10.020

    Article  CAS  PubMed  Google Scholar 

  153. Kwon I, Kato M, Xiang S et al (2013) Phosphorylation-regulated binding of RNA polymerase II to fibrous polymers of low-complexity domains. Cell 155:1049–1060. doi:10.1016/j.cell.2013.10.033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Kwon I, Xiang S, Kato M et al (2014) Poly-dipeptides encoded by the C9ORF72 repeats bind nucleoli, impede RNA biogenesis, and kill cells. Science. doi:10.1126/science.1254917

    Google Scholar 

  155. Jackrel ME, DeSantis ME, Martinez BA et al (2014) Potentiated Hsp104 variants antagonize diverse proteotoxic misfolding events. Cell 156:170–182. doi:10.1016/j.cell.2013.11.047

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Buchan JR, Kolaitis R-M, Taylor JP, 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Cirulli ET, Lasseigne BN, Petrovski S et al (2015) Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways. Science. doi:10.1126/science.aaa3650

    PubMed  PubMed Central  Google Scholar 

  158. Meyer H, Weihl CC (2014) The VCP/p97 system at a glance: connecting cellular function to disease pathogenesis. J Cell Sci 127:3877–3883. doi:10.1242/jcs.093831

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Barmada SJ, Serio A, Arjun A et al (2014) Autophagy induction enhances TDP43 turnover and survival in neuronal ALS models. Nat Chem Biol 10:677–685. doi:10.1038/nchembio.1563

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Wang I-F, Guo B-S, Liu Y-C et al (2012) Autophagy activators rescue and alleviate pathogenesis of a mouse model with proteinopathies of the TAR DNA-binding protein 43. Proc Natl Acad Sci U S A 109:15024–15029. doi:10.1073/pnas.1206362109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Wang I-F, Tsai K-J, Shen C-KJ (2013) Autophagy activation ameliorates neuronal pathogenesis of FTLD-U mice: a new light for treatment of TARDBP/TDP-43 proteinopathies. Autophagy 9:239–240. doi:10.4161/auto.22526

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Wang X, Fan H, Ying Z et al (2010) Degradation of TDP-43 and its pathogenic form by autophagy and the ubiquitin-proteasome system. Neurosci Lett 469:112–116. doi:10.1016/j.neulet.2009.11.055

    Article  CAS  PubMed  Google Scholar 

  163. Jain S, Wheeler JR, Walters RW et al. (2016) ATPase-modulated stress granules contain a diverse proteome and substructure. Cell 164:487–498. doi:10.1016/j.cell.2015.12.038.

    Article  CAS  PubMed  Google Scholar 

  164. Lin Y, Protter DSW, Rosen MK, Parker R (2015) Formation and maturation of phase-separated liquid droplets by RNA-binding proteins. Mol Cell 60:208–219. doi:10.1016/j.molcel.2015.08.018.

    Article  CAS  PubMed  Google Scholar 

  165. Zhang H, Elbaum-Garfinkle S, Langdon EM et al. (2015) RNA controls PolyQ protein phase transitions. Mol Cell 60:220–230. doi:10.1016/j.molcel.2015.09.017.

    Article  CAS  PubMed  Google Scholar 

  166. Guo L, Shorter J (2015) It’s raining liquids: RNA tunes viscoelasticity and dynamics of membraneless organelles. Mol Cell 60:189–192. doi:10.1016/j.molcel.2015.10.006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Molliex A, Temirov J, Lee J et al. (2015) Phase separation by low complexity domains promotes stress granule assembly and drives pathological fibrillization. Cell 163:123–133. doi:10.1016/j.cell.2015.09.015.

    Article  CAS  PubMed  Google Scholar 

  168. Murakami T, Qamar S, Lin JQ et al. (2015) ALS/FTD mutation-induced phase transition of FUS liquid droplets and reversible hydrogels into irreversible hydrogels impairs RNP granule function. Neuron 88:678–690. doi:10.1016/j.neuron.2015.10.030.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We would like to thank Drs. Phillip Sharp, Nancy Kedersha, Anaïs Aulas, and Voula Mili for critical reading of the manuscript, Drs. Steve McKnight and Masato Kato on sharing their insights on the role of low-complexity domains in RNA granule formation. This work was partly supported by Johns Hopkins Catalyst Award and NIH R01-GM104135 to A.K.L.L.

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  1. Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA

    Alexander C. Fan & Anthony K. L. Leung

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  1. Dept of Cellular and Molecular Medicine, Institute for Genomic Medicine, La Jolla, California, USA

    Gene W. Yeo

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Fan, A.C., Leung, A.K.L. (2016). RNA Granules and Diseases: A Case Study of Stress Granules in ALS and FTLD. In: Yeo, G. (eds) RNA Processing. Advances in Experimental Medicine and Biology, vol 907. Springer, Cham. https://doi.org/10.1007/978-3-319-29073-7_11

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