1932

Abstract

We have made rapid progress in recent years in identifying the genetic causes of many human diseases. However, despite this recent progress, our mechanistic understanding of these diseases is often incomplete. This is a problem because it limits our ability to develop effective disease treatments. To overcome this limitation, we need new concepts to describe and comprehend the complex mechanisms underlying human diseases. Condensate formation by phase separation emerges as a new principle to explain the organization of living cells. In this review, we present emerging evidence that aberrant forms of condensates are associated with many human diseases, including cancer, neurodegeneration, and infectious diseases. We examine disease mechanisms driven by aberrant condensates, and we point out opportunities for therapeutic interventions. We conclude that phase separation provides a useful new framework to understand and fight some of the most severe human diseases.

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2019-12-03
2024-04-20
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Literature Cited

  1. 1. 
    Aguzzi A, Altmeyer M. 2016. Phase separation: linking cellular compartmentalization to disease. Trends Cell Biol 26:547–58
    [Google Scholar]
  2. 2. 
    Alami NH, Smith RB, Carrasco MA, Williams LA, Winborn CS et al. 2014. Axonal transport of TDP-43 mRNA granules is impaired by ALS-causing mutations. Neuron 81:536–43
    [Google Scholar]
  3. 3. 
    Alberti S, Carra S. 2018. Quality control of membraneless organelles. J. Mol. Biol. 430:4711–29
    [Google Scholar]
  4. 4. 
    Alberti S, Gladfelter A, Mittag T 2019. Considerations and challenges in studying liquid-liquid phase separation and biomolecular condensates. Cell 176:419–34
    [Google Scholar]
  5. 5. 
    Alberti S, Halfmann R, King O, Kapila A, Lindquist S 2009. A systematic survey identifies prions and illuminates sequence features of prionogenic proteins. Cell 137:146–58
    [Google Scholar]
  6. 6. 
    Alberti S, Hyman AA. 2016. Are aberrant phase transitions a driver of cellular aging. ? Bioessays 38:959–68
    [Google Scholar]
  7. 7. 
    Alexander EJ, Ghanbari Niaki A, Zhang T, Sarkar J, Liu Y et al. 2018. Ubiquilin 2 modulates ALS/FTD-linked FUS-RNA complex dynamics and stress granule formation. PNAS 115:E11485–94
    [Google Scholar]
  8. 8. 
    Altmeyer M, Neelsen KJ, Teloni F, Pozdnyakova I, Pellegrino S et al. 2015. Liquid demixing of intrinsically disordered proteins is seeded by poly(ADP-ribose). Nat. Commun. 6:8088
    [Google Scholar]
  9. 9. 
    Ambadipudi S, Biernat J, Riedel D, Mandelkow E, Zweckstetter M 2017. Liquid-liquid phase separation of the microtubule-binding repeats of the Alzheimer-related protein Tau. Nat. Commun. 8:275
    [Google Scholar]
  10. 10. 
    Anderson P, Kedersha N. 2009. RNA granules: post-transcriptional and epigenetic modulators of gene expression. Nat. Rev. Mol. Cell Biol. 10:430–36
    [Google Scholar]
  11. 11. 
    Ash PEA, Bieniek KF, Gendron TF, Caulfield T, Lin W-L et al. 2013. Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. Neuron 77:639–46
    [Google Scholar]
  12. 12. 
    Banani SF, Lee HO, Hyman AA, Rosen MK 2017. Biomolecular condensates: organizers of cellular biochemistry. Nat. Rev. Mol. Cell Biol. 18:285–98
    [Google Scholar]
  13. 13. 
    Banani SF, Rice AM, Peeples WB, Lin Y, Jain S et al. 2016. Compositional control of phase-separated cellular bodies. Cell 166:651–63
    [Google Scholar]
  14. 14. 
    Bañez-Coronel M, Ayhan F, Tarabochia AD, Zu T, Perez BA et al. 2015. RAN translation in Huntington disease. Neuron 88:667–77
    [Google Scholar]
  15. 15. 
    Banjade S, Rosen MK. 2014. Phase transitions of multivalent proteins can promote clustering of membrane receptors. eLife 3:e04123
    [Google Scholar]
  16. 16. 
    Bentmann E, Neumann M, Tahirovic S, Rodde R, Dormann D, Haass C 2012. Requirements for stress granule recruitment of fused in sarcoma (FUS) and TAR DNA-binding protein of 43 kDa (TDP-43). J. Biol. Chem. 287:23079–94
    [Google Scholar]
  17. 17. 
    Bergeron-Sandoval LP, Heris HK, Hendricks AG 2017. Endocytosis caused by liquid-liquid phase separation of proteins. bioRxiv 145664. https://doi.org/10.1101/145664
    [Crossref]
  18. 18. 
    Beroukhim R, Mermel CH, Porter D, Wei G, Raychaudhuri S et al. 2010. The landscape of somatic copy-number alteration across human cancers. Nature 463:899–905
    [Google Scholar]
  19. 19. 
    Berry J, Weber SC, Vaidya N, Haataja M, Brangwynne CP 2015. RNA transcription modulates phase transition-driven nuclear body assembly. PNAS 112:E5237–45
    [Google Scholar]
  20. 20. 
    Bertolotti A. 2018. Importance of the subcellular location of protein deposits in neurodegenerative diseases. Curr. Opin. Neurobiol. 51:127–33
    [Google Scholar]
  21. 21. 
    Boehning M, Dugast-Darzacq C, Rankovic M, Hansen AS, Yu T-K et al. 2018. RNA polymerase II clustering through carboxy-terminal domain phase separation. Nat. Struct. Mol. Biol. 25:833–40
    [Google Scholar]
  22. 22. 
    Boeynaems S, Bogaert E, Kovacs D, Konijnenberg A, Timmerman E et al. 2017. Phase separation of C9orf72 dipeptide repeats perturbs stress granule dynamics. Mol. Cell 65:1044–55.e5
    [Google Scholar]
  23. 23. 
    Boija A, Klein IA, Sabari BR, Dall'Agnese A, Coffey EL et al. 2018. Transcription factors activate genes through the phase-separation capacity of their activation domains. Cell 175:1842–55.e16
    [Google Scholar]
  24. 24. 
    Bosco DA, Lemay N, Ko HK, Zhou H, Burke C et al. 2010. Mutant FUS proteins that cause amyotrophic lateral sclerosis incorporate into stress granules. Hum. Mol. Genet. 19:4160–75
    [Google Scholar]
  25. 25. 
    Bouchard JJ, Otero JH, Scott DC, Szulc E, Martin EW et al. 2018. Cancer mutations of the tumor suppressor SPOP disrupt the formation of active, phase-separated compartments. Mol. Cell 72:19–36.e8
    [Google Scholar]
  26. 26. 
    Boulay G, Sandoval GJ, Riggi N, Iyer S, Buisson R et al. 2017. Cancer-specific retargeting of BAF complexes by a prion-like domain. Cell 171:163–78.e19
    [Google Scholar]
  27. 27. 
    Brelstaff J, Lashley T, Holton JL, Lees AJ, Rossor MN et al. 2011. Transportin1: a marker of FTLD-FUS. Acta Neuropathol 122:591–600
    [Google Scholar]
  28. 28. 
    Brengues M, Teixeira D, Parker R 2005. Movement of eukaryotic mRNAs between polysomes and cytoplasmic processing bodies. Science 310:486–89
    [Google Scholar]
  29. 29. 
    Buchan JR, Kolaitis R-M, Taylor JP, Parker R 2013. Eukaryotic stress granules are cleared by autophagy and Cdc48/VCP function. Cell 153:1461–74
    [Google Scholar]
  30. 30. 
    Buchan JR, Parker R. 2009. Eukaryotic stress granules: the ins and outs of translation. Mol. Cell 36:932–41
    [Google Scholar]
  31. 31. 
    Chapuy B, McKeown MR, Lin CY, Monti S, Roemer MGM et al. 2013. Discovery and characterization of super-enhancer-associated dependencies in diffuse large B cell lymphoma. Cancer Cell 24:777–90
    [Google Scholar]
  32. 32. 
    Cho W-K, Spille J-H, Hecht M, Lee C, Li C et al. 2018. Mediator and RNA polymerase II clusters associate in transcription-dependent condensates. Science 361:412–15
    [Google Scholar]
  33. 33. 
    Chong PA, Vernon RM, Forman-Kay JD 2018. RGG/RG motif regions in RNA binding and phase separation. J. Mol. Biol. 430:4650–65
    [Google Scholar]
  34. 34. 
    Chong S, Dugast-Darzacq C, Liu Z, Dong P, Dailey GM et al. 2018. Imaging dynamic and selective low-complexity domain interactions that control gene transcription. Science 361:eaar2555
    [Google Scholar]
  35. 35. 
    Ciryam P, Kundra R, Morimoto RI, Dobson CM, Vendruscolo M 2015. Supersaturation is a major driving force for protein aggregation in neurodegenerative diseases. Trends Pharmacol. Sci. 36:72–77
    [Google Scholar]
  36. 36. 
    Ciryam P, Tartaglia GG, Morimoto RI, Dobson CM, Vendruscolo M 2013. Widespread aggregation and neurodegenerative diseases are associated with supersaturated proteins. Cell Rep 5:781–90
    [Google Scholar]
  37. 37. 
    Conicella AE, Zerze GH, Mittal J, Fawzi NL 2016. ALS mutations disrupt phase separation mediated by α-helical structure in the TDP-43 low-complexity C-terminal domain. Structure 24:1537–49
    [Google Scholar]
  38. 38. 
    Crozat A, Aman P, Mandahl N, Ron D 1993. Fusion of CHOP to a novel RNA-binding protein in human myxoid liposarcoma. Nature 363:640–44
    [Google Scholar]
  39. 39. 
    Dao TP, Kolaitis R-M, Kim HJ, O'Donovan K, Martyniak B et al. 2018. Ubiquitin modulates liquid-liquid phase separation of UBQLN2 via disruption of multivalent interactions. Mol. Cell 69:965–78.e6
    [Google Scholar]
  40. 40. 
    Das RK, Ruff KM, Pappu RV 2015. Relating sequence encoded information to form and function of intrinsically disordered proteins. Curr. Opin. Struct. Biol. 32:102–12
    [Google Scholar]
  41. 41. 
    Davidson YS, Robinson AC, Hu Q, Mishra M, Baborie A et al. 2013. Nuclear carrier and RNA-binding proteins in frontotemporal lobar degeneration associated with fused in sarcoma (FUS) pathological changes. Neuropathol. Appl. Neurobiol. 39:157–65
    [Google Scholar]
  42. 42. 
    DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M et al. 2011. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72:245–56
    [Google Scholar]
  43. 43. 
    Dewey CM, Cenik B, Sephton CF, Dries DR, Mayer P 3rd et al. 2011. TDP-43 is directed to stress granules by sorbitol, a novel physiological osmotic and oxidative stressor. Mol. Cell. Biol. 31:1098–108
    [Google Scholar]
  44. 44. 
    Dormann D, Madl T, Valori CF, Bentmann E, Tahirovic S et al. 2012. Arginine methylation next to the PY-NLS modulates transportin binding and nuclear import of FUS. EMBO J 31:4258–75
    [Google Scholar]
  45. 45. 
    Dormann D, Rodde R, Edbauer D, Bentmann E, Fischer I et al. 2010. ALS-associated fused in sarcoma (FUS) mutations disrupt Transportin-mediated nuclear import. EMBO J 29:2841–57
    [Google Scholar]
  46. 46. 
    Du M, Chen ZJ. 2018. DNA-induced liquid phase condensation of cGAS activates innate immune signaling. Science 361:704–9
    [Google Scholar]
  47. 47. 
    Ellis RJ. 2001. Macromolecular crowding: an important but neglected aspect of the intracellular environment. Curr. Opin. Struct. Biol. 11:114–19
    [Google Scholar]
  48. 48. 
    Falahati H, Wieschaus E. 2017. Independent active and thermodynamic processes govern the nucleolus assembly in vivo. PNAS 114:1335–40
    [Google Scholar]
  49. 49. 
    Felsher DW, Bishop JM. 1999. Reversible tumorigenesis by MYC in hematopoietic lineages. Mol. Cell 4:199–207
    [Google Scholar]
  50. 50. 
    Feric M, Vaidya N, Harmon TS, Mitrea DM, Zhu L et al. 2016. Coexisting liquid phases underlie nucleolar subcompartments. Cell 165:1686–97
    [Google Scholar]
  51. 51. 
    Fisher RA, Gollan B, Helaine S 2017. Persistent bacterial infections and persister cells. Nat. Rev. Microbiol. 15:453–64
    [Google Scholar]
  52. 52. 
    Forman-Kay JD, Kriwacki RW, Seydoux G 2018. Phase separation in biology and disease. J. Mol. Biol. 430:4603–6
    [Google Scholar]
  53. 53. 
    Franzmann T, Alberti S. 2018. Prion-like low-complexity sequences: key regulators of protein solubility and phase behavior. J. Biol. Chem. https://doi.org/10.1074/jbc.TM118.001190
    [Crossref] [Google Scholar]
  54. 54. 
    Franzmann TM, Alberti S. 2019. Protein phase separation as a stress survival strategy. Cold Spring Harb. Perspect. Biol. https://doi.org/10.1101/cshperspect.a034058
    [Crossref] [Google Scholar]
  55. 55. 
    Franzmann TM, Jahnel M, Pozniakovsky A, Mahamid J, Holehouse AS et al. 2018. Phase separation of a yeast prion protein promotes cellular fitness. Science 359:eaao5654
    [Google Scholar]
  56. 56. 
    Gan L, Cookson MR, Petrucelli L, La Spada AR 2018. Converging pathways in neurodegeneration, from genetics to mechanisms. Nat. Neurosci. 21:1300–9
    [Google Scholar]
  57. 57. 
    Ganassi M, Mateju D, Bigi I, Mediani L, Poser I et al. 2016. A surveillance function of the HSPB8-BAG3-HSP70 chaperone complex ensures stress granule integrity and dynamism. Mol. Cell 63:796–810
    [Google Scholar]
  58. 58. 
    Gatchel JR, Zoghbi HY. 2005. Diseases of unstable repeat expansion: mechanisms and common principles. Nat. Rev. Genet. 6:743–55
    [Google Scholar]
  59. 59. 
    Gopal PP, Nirschl JJ, Klinman E, Holzbaur ELF 2017. Amyotrophic lateral sclerosis-linked mutations increase the viscosity of liquid-like TDP-43 RNP granules in neurons. PNAS 114:E2466–75
    [Google Scholar]
  60. 60. 
    Guo L, Kim HJ, Wang H, Monaghan J, Freyermuth F et al. 2018. Nuclear-import receptors reverse aberrant phase transitions of RNA-binding proteins with prion-like domains. Cell 173:677–92.e20
    [Google Scholar]
  61. 61. 
    Hanahan D, Weinberg RA. 2011. Hallmarks of cancer: the next generation. Cell 144:646–74
    [Google Scholar]
  62. 62. 
    Harmon TS, Holehouse AS, Rosen MK, Pappu RV 2017. Intrinsically disordered linkers determine the interplay between phase separation and gelation in multivalent proteins. eLife 6:e30294
    [Google Scholar]
  63. 63. 
    Hasegawa M, Arai T, Nonaka T, Kametani F, Yoshida M et al. 2008. Phosphorylated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Ann. Neurol. 64:60–70
    [Google Scholar]
  64. 64. 
    Hayden E, Cone A, Ju S 2017. Supersaturated proteins in ALS. PNAS 114:5065–66
    [Google Scholar]
  65. 65. 
    Hayes MH, Peuchen EH, Dovichi NJ, Weeks DL 2018. Dual roles for ATP in the regulation of phase separated protein aggregates in Xenopus oocyte nucleoli. eLife 7:e35224
    [Google Scholar]
  66. 66. 
    Heinrich BS, Maliga Z, Stein DA, Hyman AA, Whelan SPJ 2018. Phase transitions drive the formation of vesicular stomatitis virus replication compartments. mBio 9:e02290–17
    [Google Scholar]
  67. 67. 
    Hernández-Vega A, Braun M, Scharrel L, Jahnel M, Wegmann S et al. 2017. Local nucleation of microtubule bundles through tubulin concentration into a condensed Tau phase. Cell Rep 20:2304–12
    [Google Scholar]
  68. 68. 
    Hnisz D, Abraham BJ, Lee TI, Lau A, Saint-André V et al. 2013. Super-enhancers in the control of cell identity and disease. Cell 155:934–47
    [Google Scholar]
  69. 69. 
    Hnisz D, Schuijers J, Lin CY, Weintraub AS, Abraham BJ et al. 2015. Convergence of developmental and oncogenic signaling pathways at transcriptional super-enhancers. Mol. Cell 58:362–70
    [Google Scholar]
  70. 70. 
    Hnisz D, Shrinivas K, Young RA, Chakraborty AK, Sharp PA 2017. A phase separation model for transcriptional control. Cell 169:13–23
    [Google Scholar]
  71. 71. 
    Hofweber M, Dormann D. 2018. Friend or foe—post-translational modifications as regulators of phase separation and RNP granule dynamics. J. Biol. Chem. https://doi.org/10.1074/jbc.TM118.001189
    [Crossref] [Google Scholar]
  72. 72. 
    Hofweber M, Hutten S, Bourgeois B, Spreitzer E, Niedner-Boblenz A et al. 2018. Phase separation of FUS is suppressed by its nuclear import receptor and arginine methylation. Cell 173:706–19.e13
    [Google Scholar]
  73. 73. 
    Holt CE, Schuman EM. 2013. The central dogma decentralized: new perspectives on RNA function and local translation in neurons. Neuron 80:648–57
    [Google Scholar]
  74. 74. 
    Hubstenberger A, Noble SL, Cameron C, Evans TC 2013. Translation repressors, an RNA helicase, and developmental cues control RNP phase transitions during early development. Dev. Cell 27:161–73
    [Google Scholar]
  75. 75. 
    Hyman AA, Weber CA, Jülicher F 2014. Liquid-liquid phase separation in biology. Annu. Rev. Cell Dev. Biol. 30:39–58
    [Google Scholar]
  76. 76. 
    Jain A, Vale RD. 2017. RNA phase transitions in repeat expansion disorders. Nature 546:243–47
    [Google Scholar]
  77. 77. 
    Jain M, Arvanitis C, Chu K, Dewey W, Leonhardt E et al. 2002. Sustained loss of a neoplastic phenotype by brief inactivation of MYC. Science 297:102–4
    [Google Scholar]
  78. 78. 
    Jain S, Wheeler JR, Walters RW, Agrawal A, Barsic A, Parker R 2016. ATPase-modulated stress granules contain a diverse proteome and substructure. Cell 164:487–98
    [Google Scholar]
  79. 79. 
    Jäkel S, Mingot J-M, Schwarzmaier P, Hartmann E, Görlich D 2002. Importins fulfill a dual function as nuclear import receptors and cytoplasmic chaperones for exposed basic domains. EMBO J 21:377–86
    [Google Scholar]
  80. 80. 
    Jensen MR, Ruigrok RWH, Blackledge M 2013. Describing intrinsically disordered proteins at atomic resolution by NMR. Curr. Opin. Struct. Biol. 23:426–35
    [Google Scholar]
  81. 81. 
    Jucker M, Walker LC. 2018. Propagation and spread of pathogenic protein assemblies in neurodegenerative diseases. Nat. Neurosci. 21:1341–49
    [Google Scholar]
  82. 82. 
    Kametani F, Obi T, Shishido T, Akatsu H, Murayama S et al. 2016. Mass spectrometric analysis of accumulated TDP-43 in amyotrophic lateral sclerosis brains. Sci. Rep. 6:23281
    [Google Scholar]
  83. 83. 
    Kandel ER, Dudai Y, Mayford MR 2014. The molecular and systems biology of memory. Cell 157:163–86
    [Google Scholar]
  84. 84. 
    Kedersha N, Panas MD, Achorn CA, Lyons S, Tisdale S et al. 2016. G3BP–Caprin1–USP10 complexes mediate stress granule condensation and associate with 40S subunits. J. Cell Biol. 212:845–60
    [Google Scholar]
  85. 85. 
    Kedersha NL, Gupta M, Li W, Miller I, Anderson P 1999. RNA-binding proteins TIA-1 and TIAR link the phosphorylation of eIF-2α to the assembly of mammalian stress granules. J. Cell Biol. 147:1431–42
    [Google Scholar]
  86. 86. 
    Khan T, Kandola TS, Wu J, Venkatesan S, Ketter E et al. 2018. Quantifying nucleation in vivo reveals the physical basis of prion-like phase behavior. Mol. Cell 71:155–68.e7
    [Google Scholar]
  87. 87. 
    Kiebler MA, Scheiffele P, Ule J 2013. What, where, and when: the importance of post-transcriptional regulation in the brain. Front. Neurosci. 7:192
    [Google Scholar]
  88. 88. 
    Kim HJ, Kim NC, Wang Y-D, Scarborough EA, Moore J et al. 2013. Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature 495:467–73
    [Google Scholar]
  89. 89. 
    Kroschwald S, Maharana S, Mateju D, Malinovska L, Nüske E et al. 2015. Promiscuous interactions and protein disaggregases determine the material state of stress-inducible RNP granules. eLife 4:e06807
    [Google Scholar]
  90. 90. 
    Kroschwald S, Munder MC, Maharana S, Franzmann TM, Richter D et al. 2018. Different material states of Pub1 condensates define distinct modes of stress adaptation and recovery. Cell Rep 23:3327–39
    [Google Scholar]
  91. 91. 
    Kwon I, Kato M, Xiang S, Wu L, Theodoropoulos P et al. 2013. Phosphorylation-regulated binding of RNA polymerase II to fibrous polymers of low-complexity domains. Cell 155:1049–60
    [Google Scholar]
  92. 92. 
    Langdon EM, Qiu Y, Ghanbari Niaki A, McLaughlin GA, Weidmann C et al. 2018. mRNA structure determines specificity of a polyQ-driven phase separation. Science 360:922–27
    [Google Scholar]
  93. 93. 
    Larson AG, Elnatan D, Keenen MM, Trnka MJ, Johnston JB et al. 2017. Liquid droplet formation by HP1α suggests a role for phase separation in heterochromatin. Nature 547:236–40
    [Google Scholar]
  94. 94. 
    Lee K-H, Zhang P, Kim HJ, Mitrea DM, Sarkar M et al. 2016. C9orf72 dipeptide repeats impair the assembly, dynamics, and function of membrane-less organelles. Cell 167:774–88.e17
    [Google Scholar]
  95. 95. 
    Lemmon MA, Schlessinger J. 2010. Cell signaling by receptor tyrosine kinases. Cell 141:1117–34
    [Google Scholar]
  96. 96. 
    Li P, Banjade S, Cheng H-C, Kim S, Chen B et al. 2012. Phase transitions in the assembly of multivalent signalling proteins. Nature 483:336–40
    [Google Scholar]
  97. 97. 
    Lin Y, Mori E, Kato M, Xiang S, Wu L et al. 2016. Toxic PR poly-dipeptides encoded by the C9orf72 repeat expansion target LC domain polymers. Cell 167:789–802.e12
    [Google Scholar]
  98. 98. 
    Liu-Yesucevitz L, Bilgutay A, Zhang Y-J, Vanderwyde T, Citro A 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
    [Google Scholar]
  99. 99. 
    Mackenzie IR, Nicholson AM, Sarkar M, Messing J, Purice MD et al. 2017. TIA1 mutations in amyotrophic lateral sclerosis and frontotemporal dementia promote phase separation and alter stress granule dynamics. Neuron 95:808–16.e9
    [Google Scholar]
  100. 100. 
    Maharana S, Wang J, Papadopoulos DK, Richter D, Pozniakovsky A et al. 2018. RNA buffers the phase separation behavior of prion-like RNA binding proteins. Science 360:918–21
    [Google Scholar]
  101. 101. 
    March ZM, King OD, Shorter J 2016. Prion-like domains as epigenetic regulators, scaffolds for subcellular organization, and drivers of neurodegenerative disease. Brain Res 1647:9–18
    [Google Scholar]
  102. 102. 
    Marzahn MR, Marada S, Lee J, Nourse A, Kenrick S et al. 2016. Higher‐order oligomerization promotes localization of SPOP to liquid nuclear speckles. EMBO J 35:1254–75
    [Google Scholar]
  103. 103. 
    Mateju D, Franzmann TM, Patel A, Kopach A, Boczek EE et al. 2017. An aberrant phase transition of stress granules triggered by misfolded protein and prevented by chaperone function. EMBO J 36:1669–87
    [Google Scholar]
  104. 104. 
    Maziuk BF, Apicco DJ, Cruz AL, Jiang L, Ash PEA et al. 2018. RNA binding proteins co-localize with small tau inclusions in tauopathy. Acta Neuropathol. Commun. 6:71
    [Google Scholar]
  105. 105. 
    McGurk L, Gomes E, Guo L, Mojsilovic-Petrovic J, Tran V et al. 2018. Poly(ADP-ribose) prevents pathological phase separation of TDP-43 by promoting liquid demixing and stress granule localization. Mol. Cell 71:703–17.e9
    [Google Scholar]
  106. 106. 
    McGurk L, Mojsilovic-Petrovic J, Van Deerlin VM, Shorter J, Kalb RG et al. 2018. Nuclear poly(ADP-ribose) activity is a therapeutic target in amyotrophic lateral sclerosis. Acta Neuropathol. Commun. 6:84
    [Google Scholar]
  107. 107. 
    Mitrea DM, Cika JA, Guy CS, Ban D, Banerjee PR et al. 2016. Nucleophosmin integrates within the nucleolus via multi-modal interactions with proteins displaying R-rich linear motifs and rRNA. eLife 5:e13571
    [Google Scholar]
  108. 108. 
    Molliex A, Temirov J, Lee J, Coughlin M, Kanagaraj AP et al. 2015. Phase separation by low complexity domains promotes stress granule assembly and drives pathological fibrillization. Cell 163:123–33
    [Google Scholar]
  109. 109. 
    Monahan Z, Ryan VH, Janke AM, Burke KA, Rhoads SN et al. 2017. Phosphorylation of the FUS low-complexity domain disrupts phase separation, aggregation, and toxicity. EMBO J 36:2951–67
    [Google Scholar]
  110. 110. 
    Mori K, Weng S-M, Arzberger T, May S, Rentzsch K et al. 2013. The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science 339:1335–38
    [Google Scholar]
  111. 111. 
    Munder MC, Midtvedt D, Franzmann T, Nüske E, Otto O et al. 2016. A pH-driven transition of the cytoplasm from a fluid- to a solid-like state promotes entry into dormancy. eLife 5:e09347
    [Google Scholar]
  112. 112. 
    Murakami T, Qamar S, Lin JQ, Schierle GSK, Rees E et al. 2015. ALS/FTD mutation-induced phase transition of FUS liquid droplets and reversible hydrogels into irreversible hydrogels impairs RNP granule function. Neuron 88:678–90
    [Google Scholar]
  113. 113. 
    Nadezhdina ES, Lomakin AJ, Shpilman AA, Chudinova EM, Ivanov PA 2010. Microtubules govern stress granule mobility and dynamics. Biochim. Biophys. Acta Mol. Cell Res. 1803:361–71
    [Google Scholar]
  114. 114. 
    Netherton CL, Wileman T. 2011. Virus factories, double membrane vesicles and viroplasm generated in animal cells. Curr. Opin. Virol. 1:381–87
    [Google Scholar]
  115. 115. 
    Niccoli T, Partridge L. 2012. Ageing as a risk factor for disease. Curr. Biol. 22:R741–52
    [Google Scholar]
  116. 116. 
    Nikolic J, Le Bars R, Lama Z, Scrima N, Lagaudrière-Gesbert C et al. 2017. Negri bodies are viral factories with properties of liquid organelles. Nat. Commun. 8:58
    [Google Scholar]
  117. 117. 
    Nott TJ, Craggs TD, Baldwin AJ 2016. Membraneless organelles can melt nucleic acid duplexes and act as biomolecular filters. Nat. Chem. 8:569–75
    [Google Scholar]
  118. 118. 
    Nott TJ, Petsalaki E, Farber P, Jervis D, Fussner E et al. 2015. Phase transition of a disordered nuage protein generates environmentally responsive membraneless organelles. Mol. Cell 57:936–47
    [Google Scholar]
  119. 119. 
    Novoa RR, Calderita G, Arranz R, Fontana J, Granzow H, Risco C 2005. Virus factories: associations of cell organelles for viral replication and morphogenesis. Biol. Cell 97:147–72
    [Google Scholar]
  120. 120. 
    Oltsch F, Klosin A, Julicher F, Hyman AA, Zechner C 2019. Phase separation provides a mechanism to reduce noise in cells. bioRxiv 524231. https://doi.org/10.1101/524231
    [Crossref]
  121. 121. 
    Onomoto K, Yoneyama M, Fung G, Kato H, Fujita T 2014. Antiviral innate immunity and stress granule responses. Trends Immunol 35:420–28
    [Google Scholar]
  122. 122. 
    Parry BR, Surovtsev IV, Cabeen MT, O'Hern CS, Dufresne ER, Jacobs-Wagner C 2014. The bacterial cytoplasm has glass-like properties and is fluidized by metabolic activity. Cell 156:183–94
    [Google Scholar]
  123. 123. 
    Patel A, Lee HO, Jawerth L, Maharana S, Jahnel M et al. 2015. A liquid-to-solid phase transition of the ALS protein FUS accelerated by disease mutation. Cell 162:1066–77
    [Google Scholar]
  124. 124. 
    Patel A, Malinovska L, Saha S, Wang J, Alberti S et al. 2017. ATP as a biological hydrotrope. Science 356:753–56
    [Google Scholar]
  125. 125. 
    Peskett TR, Rau F, O'Driscoll J, Patani R, Lowe AR, Saibil HR 2018. A liquid to solid phase transition underlying pathological huntingtin exon1 aggregation. Mol. Cell 70:588–601.e6
    [Google Scholar]
  126. 126. 
    Poblete-Durán N, Prades-Pérez Y, Vera-Otarola J, Soto-Rifo R, Valiente-Echeverría F 2016. Who regulates whom? An overview of RNA granules and viral infections. Viruses 8:E180
    [Google Scholar]
  127. 127. 
    Qamar S, Wang G, Randle SJ, Ruggeri FS, Varela JA et al. 2018. FUS phase separation is modulated by a molecular chaperone and methylation of arginine cation-π interactions. Cell 173:720–34.e15
    [Google Scholar]
  128. 128. 
    Rabouille C, Alberti S. 2017. Cell adaptation upon stress: the emerging role of membrane-less compartments. Curr. Opin. Cell Biol. 47:34–42
    [Google Scholar]
  129. 129. 
    Raichle ME, Gusnard DA. 2002. Appraising the brain's energy budget. PNAS 99:10237–39
    [Google Scholar]
  130. 130. 
    Rappsilber J, Friesen WJ, Paushkin S, Dreyfuss G, Mann M 2003. Detection of arginine dimethylated peptides by parallel precursor ion scanning mass spectrometry in positive ion mode. Anal. Chem. 75:3107–14
    [Google Scholar]
  131. 131. 
    Renton AE, Majounie E, Waite A, Simón-Sánchez J, Rollinson S et al. 2011. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72:257–68
    [Google Scholar]
  132. 132. 
    Riback JA, Katanski CD, Kear-Scott JL, Pilipenko EV, Rojek AE et al. 2017. Stress-triggered phase separation is an adaptive, evolutionarily tuned response. Cell 168:1028–40.e19
    [Google Scholar]
  133. 133. 
    Rubinstein M, Dobrynin AV. 1997. Solutions of associative polymers. Trends Polymer Sci 5:181–86
    [Google Scholar]
  134. 134. 
    Sabari BR, Dall'Agnese A, Boija A, Klein IA, Coffey EL et al. 2018. Coactivator condensation at super-enhancers links phase separation and gene control. Science 361:eaar3958
    [Google Scholar]
  135. 135. 
    Schmid M, Speiseder T, Dobner T, Gonzalez RA 2014. DNA virus replication compartments. J. Virol. 88:1404–20
    [Google Scholar]
  136. 136. 
    Schmidt HB, Görlich D. 2016. Transport selectivity of nuclear pores, phase separation, and membraneless organelles. Trends Biochem. Sci. 41:46–61
    [Google Scholar]
  137. 137. 
    Semenov AN, Rubinstein M. 1998. Thermoreversible gelation in solutions of associative polymers. 1. Statics. Macromolecules 31:1373–85
    [Google Scholar]
  138. 138. 
    Shin Y, Brangwynne CP. 2017. Liquid phase condensation in cell physiology and disease. Science 357:eaaf4382
    [Google Scholar]
  139. 139. 
    So M, Hall D, Goto Y 2016. Revisiting supersaturation as a factor determining amyloid fibrillation. Curr. Opin. Struct. Biol. 36:32–39
    [Google Scholar]
  140. 140. 
    Soucek L, Whitfield J, Martins CP, Finch AJ, Murphy DJ et al. 2008. Modelling Myc inhibition as a cancer therapy. Nature 455:679–83
    [Google Scholar]
  141. 141. 
    Strom AR, Emelyanov AV, Mir M, Fyodorov DV, Darzacq X, Karpen GH 2017. Phase separation drives heterochromatin domain formation. Nature 547:241–45
    [Google Scholar]
  142. 142. 
    Su X, Ditlev JA, Hui E, Xing W, Banjade S et al. 2016. Phase separation of signaling molecules promotes T cell receptor signal transduction. Science 352:595–99
    [Google Scholar]
  143. 143. 
    Suárez-Calvet M, Neumann M, Arzberger T, Abou-Ajram C, Funk E et al. 2016. Monomethylated and unmethylated FUS exhibit increased binding to Transportin and distinguish FTLD-FUS from ALS-FUS. Acta Neuropathol 131:587–604
    [Google Scholar]
  144. 144. 
    Taylor JP, Brown RH Jr, Cleveland DW 2016. Decoding ALS: from genes to mechanism. Nature 539:197–206
    [Google Scholar]
  145. 145. 
    Taylor JP, Hardy J, Fischbeck KH 2002. Toxic proteins in neurodegenerative disease. Science 296:1991–95
    [Google Scholar]
  146. 146. 
    Tourrière H, Chebli K, Zekri L, Courselaud B, Blanchard JM et al. 2003. The RasGAP-associated endoribonuclease G3BP assembles stress granules. J. Cell Biol. 160:823–31
    [Google Scholar]
  147. 147. 
    Tsai W-C, Lloyd RE. 2014. Cytoplasmic RNA granules and viral infection. Annu. Rev. Virol. 1:147–70
    [Google Scholar]
  148. 148. 
    Tsang B, Arsenault J, Vernon RM, Lin H, Sonenberg N et al. 2019. Phosphoregulated FMRP phase separation models activity-dependent translation through bidirectional control of mRNA granule formation. PNAS 116:4218–27
    [Google Scholar]
  149. 149. 
    Van Treeck B, Protter DSW, Matheny T, Khong A, Link CD, Parker R 2018. RNA self-assembly contributes to stress granule formation and defining the stress granule transcriptome. PNAS 115:2734–39
    [Google Scholar]
  150. 150. 
    Vanderweyde T, Apicco DJ, Youmans-Kidder K, Ash PEA, Cook C et al. 2016. Interaction of tau with the RNA-binding protein TIA1 regulates tau pathophysiology and toxicity. Cell Rep 15:1455–66
    [Google Scholar]
  151. 151. 
    Vanderweyde T, Yu H, Varnum M, Liu-Yesucevitz L, Citro A et al. 2012. Contrasting pathology of the stress granule proteins TIA-1 and G3BP in tauopathies. J. Neurosci. 32:8270–83
    [Google Scholar]
  152. 152. 
    Wang J, Choi J-M, Holehouse AS, Lee HO, Zhang X et al. 2018. A molecular grammar governing the driving forces for phase separation of prion-like RNA binding proteins. Cell 174:688–99.e16
    [Google Scholar]
  153. 153. 
    Wegmann S, Eftekharzadeh B, Tepper K, Zoltowska KM, Bennett RE et al. 2018. Tau protein liquid-liquid phase separation can initiate tau aggregation. EMBO J 37:e98049
    [Google Scholar]
  154. 154. 
    Whyte WA, Orlando DA, Hnisz D, Abraham BJ, Lin CY et al. 2013. Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell 153:307–19
    [Google Scholar]
  155. 155. 
    Woodruff JB, Ferreira Gomes B, Widlund PO, Mahamid J, Honigmann A, Hyman AA 2017. The centrosome is a selective condensate that nucleates microtubules by concentrating tubulin. Cell 169:1066–77.e10
    [Google Scholar]
  156. 156. 
    Yoshizawa T, Ali R, Jiou J, Fung HYJ, Burke KA et al. 2018. Nuclear import receptor inhibits phase separation of FUS through binding to multiple sites. Cell 173:693–705.e22
    [Google Scholar]
  157. 157. 
    Zhang X, Lin Y, Eschmann NA, Zhou H, Rauch JN et al. 2017. RNA stores tau reversibly in complex coacervates. PLOS Biol 15:e2002183
    [Google Scholar]
  158. 158. 
    Zu T, Gibbens B, Doty NS, Gomes-Pereira M, Huguet A et al. 2011. Non-ATG–initiated translation directed by microsatellite expansions. PNAS 108:260–65
    [Google Scholar]
  159. 159. 
    Zu T, Pattamatta A, Ranum LPW 2018. Repeat-associated non-ATG translation in neurological diseases. Cold Spring Harb. Perspect. Biol. 10:a033019
    [Google Scholar]
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