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
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
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
Bono F, Gehring NH (2011) Assembly, disassembly and recycling: the dynamics of exon junction complexes. RNA Biol 8:24–29
Schoenberg DR, Maquat LE (2012) Regulation of cytoplasmic mRNA decay. Nat Rev Genet 13:246–259. doi:10.1038/nrg3160
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
Anderson P, Kedersha NL (2006) RNA granules. J Cell Biol 172:803–808. doi:10.1083/jcb.200512082
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
Spector DL (2006) SnapShot: cellular bodies. Cell 127:1071. doi:10.1016/j.cell.2006.11.026
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
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
Collier NC, Schlesinger MJ (1986) The dynamic state of heat shock proteins in chicken embryo fibroblasts. J Cell Biol 103:1495–1507
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
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
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
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
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
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
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
Kedersha NL, Anderson P (2007) Mammalian stress granules and processing bodies. Methods Enzymol 431:61–81. doi:10.1016/S0076-6879(07)31005-7
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Kedersha NL, Anderson P (2002) Stress granules: sites of mRNA triage that regulate mRNA stability and translatability. Biochem Soc Trans 30:963–969
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Banjade S, Rosen MK (2014) Phase transitions of multivalent proteins can promote clustering of membrane receptors. Elife. doi:10.7554/eLife.04123
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
Brangwynne CP (2013) Phase transitions and size scaling of membrane-less organelles. J Cell Biol 203:875–881. doi:10.1083/jcb.201308087
Hyman AA, Simons K (2012) Cell biology. Beyond oil and water—phase transitions in cells. Science 337:1047–1049. doi:10.1126/science.1223728
Weber SC, Brangwynne CP (2012) Getting RNA and protein in phase. Cell 149:1188–1191. doi:10.1016/j.cell.2012.05.022
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
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
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
Shevtsov SP, Dundr M (2011) Nucleation of nuclear bodies by RNA. Nat Cell Biol 13:167–173. doi:10.1038/ncb2157
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
Leung AKL (2014) Poly(ADP-ribose): an organizer of cellular architecture. J Cell Biol 205:613–619. doi:10.1083/jcb.201402114
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
Shorter J, Lindquist S (2005) Prions as adaptive conduits of memory and inheritance. Nat Rev Genet 6:435–450. doi:10.1038/nrg1616
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
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
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
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
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
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
Glover JR, Lindquist S (1998) Hsp104, Hsp70, and Hsp40: a novel chaperone system that rescues previously aggregated proteins. Cell 94:73–82
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
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
Rikhvanov EG, Romanova NV, Chernoff YO (2007) Chaperone effects on prion and nonprion aggregates. Prion 1:217–222
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
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
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
Hottiger MO, Hassa PO, LĂĽscher B et al (2010) Toward a unified nomenclature for mammalian ADP-ribosyltransferases. Trends Biochem Sci. doi:10.1016/j.tibs.2009.12.003
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
Rowland LP, Shneider NA (2001) Amyotrophic lateral sclerosis. N Engl J Med 344:1688–1700. doi:10.1056/NEJM200105313442207
Rabinovici GD, Miller BL (2010) Frontotemporal lobar degeneration: epidemiology, pathophysiology, diagnosis and management. CNS Drugs 24:375–398. doi:10.2165/11533100-000000000-00000
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
Robberecht W, Philips T (2013) The changing scene of amyotrophic lateral sclerosis. Nat Rev Neurosci 14:248–264. doi:10.1038/nrn3430
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Andersson MK, StĂĄhlberg 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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Beal MF (2002) Oxidatively modified proteins in aging and disease. Free Radic Biol Med 32:797–803
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
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
Bogdanov M, Brown RH, Matson W et al (2000) Increased oxidative damage to DNA in ALS patients. Free Radic Biol Med 29:652–658
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
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
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
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
Weiduschat N et al (2014) Motor cortex glutathione deficit in ALS measured in vivo with the J-editing technique. Neurosci Lett 570:102–107
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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.
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.
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.
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.
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.
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.
Acknowledgements
We would like to thank Drs. Phillip Sharp, Nancy Kedersha, AnaĂŻs 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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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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