Bridging biophysics and neurology: aberrant phase transitions in neurodegenerative disease

Abstract

Biomolecular condensation arising through phase transitions has emerged as an essential organizational strategy that governs many aspects of cell biology. In particular, the role of phase transitions in the assembly of large, complex ribonucleoprotein (RNP) granules has become appreciated as an important regulator of RNA metabolism. In parallel, genetic, histopathological and cell and molecular studies have provided evidence that disturbance of phase transitions is an important driver of neurological diseases, notably amyotrophic lateral sclerosis (ALS), but most likely also other diseases. Indeed, our growing knowledge of the biophysics underlying biological phase transitions suggests that this process offers a unifying mechanism to explain the numerous and diverse disturbances in RNA metabolism that have been observed in ALS and some related diseases — specifically, that these diseases are driven by disturbances in the material properties of RNP granules. Here, we review the evidence for this hypothesis, emphasizing the reciprocal roles in which disease-related protein and disease-related RNA can lead to disturbances in the material properties of RNP granules and consequent pathogenesis. Additionally, we review evidence that implicates aberrant phase transitions as a contributing factor to a larger set of neurodegenerative diseases, including frontotemporal dementia, certain repeat expansion diseases and Alzheimer disease.

Key points

  • Intracellular phase transition describes a biophysical phenomenon in which macromolecules separate from their aqueous surroundings to form a functional compartment.

  • Biomolecular condensation arising through phase transitions is a cellular organizational strategy that governs many aspects of cell biology.

  • Among the largest biomolecular condensates are ribonucleoprotein (RNP) granules — membraneless organelles composed of RNA and protein — which regulate nearly all aspects of RNA metabolism.

  • Genetic, histopathological, cellular and molecular studies of amyotrophic lateral sclerosis (ALS) and related diseases have identified dysfunction in diverse aspects of RNA metabolism as a common theme.

  • Aberrant phase transitions and disturbances of the material properties of RNP granules offer a unifying mechanism for the numerous disturbances in RNA metabolism observed in ALS and related diseases.

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Fig. 1: Clinical and genetic overlap among ALS, FTD and IBM.
Fig. 2: Phase transitions as the basis of functional biomolecular condensates.
Fig. 3: Forces underlying the assembly of RNP granules.
Fig. 4: Adhesive forces underlying phase transitions.
Fig. 5: TDP43 protein and C9orf72 RNA pathology in human tissues.
Fig. 6: RNP granules are associated with pathology in both the nucleus and the cytosol.

References

  1. 1.

    Ghasemi, M. & Brown, R. H. Jr. Genetics of amyotrophic lateral sclerosis. Cold Spring Harb. Perspect. Med. 8, a024125 (2018).

    PubMed  Google Scholar 

  2. 2.

    Taylor, J. P., Brown, R. H. Jr & Cleveland, D. W. Decoding ALS: from genes to mechanism. Nature 539, 197–206 (2016).

    PubMed  PubMed Central  Google Scholar 

  3. 3.

    Barmada, S. J. Linking RNA dysfunction and neurodegeneration in amyotrophic lateral sclerosis. Neurotherapeutics 12, 340–351 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Sreedharan, J. et al. TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319, 1668–1672 (2008).

    CAS  PubMed  Google Scholar 

  5. 5.

    Kabashi, E. et al. TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat. Genet. 40, 572–574 (2008).

    CAS  PubMed  Google Scholar 

  6. 6.

    Vance, C. et al. Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science 323, 1208–1211 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Kwiatkowski, T. J. Jr. et al. Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science 323, 1205–1208 (2009).

    CAS  PubMed  Google Scholar 

  8. 8.

    Kim, H. J. et al. Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature 495, 467–473 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Liu, Q. et al. Whole-exome sequencing identifies a missense mutation in hnRNPA1 in a family with flail arm ALS. Neurology 87, 1763–1769 (2016).

    CAS  PubMed  Google Scholar 

  10. 10.

    Vieira, N. M. et al. A defect in the RNA-processing protein HNRPDL causes limb-girdle muscular dystrophy 1G (LGMD1G). Hum. Mol. Genet. 23, 4103–4110 (2014).

    CAS  PubMed  Google Scholar 

  11. 11.

    Johnson, J. O. et al. Mutations in the matrin 3 gene cause familial amyotrophic lateral sclerosis. Nat. Neurosci. 17, 664–666 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Mackenzie, I. R. et al. TIA1 mutations in amyotrophic lateral sclerosis and frontotemporal dementia promote phase separation and alter stress granule dynamics. Neuron 95, 808–816 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Smith, B. N. et al. Mutations in the vesicular trafficking protein annexin A11 are associated with amyotrophic lateral sclerosis. Sci. Transl Med. 9, eaad9157 (2017).

    PubMed  Google Scholar 

  14. 14.

    Buchan, J. R. mRNP granules. Assembly, function, and connections with disease. RNA Biol. 11, 1019–1030 (2014).

    PubMed  PubMed Central  Google Scholar 

  15. 15.

    Gomes, E. & Shorter, J. The molecular language of membraneless organelles. J. Biol. Chem. https://doi.org/10.1074/jbc.TM118.001192 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Dundr, M. Nuclear bodies: multifunctional companions of the genome. Curr. Opin. Cell Biol. 24, 415–422 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Kiebler, M. A. & Bassell, G. J. Neuronal RNA granules: movers and makers. Neuron 51, 685–690 (2006).

    CAS  PubMed  Google Scholar 

  18. 18.

    Shin, Y. & Brangwynne, C. P. Liquid phase condensation in cell physiology and disease. Science 357, eaaf4382 (2017).

    Google Scholar 

  19. 19.

    Langdon, E. M. & Gladfelter, A. S. A new lens for RNA localization: liquid-liquid phase separation. Annu. Rev. Microbiol. 72, 255–271 (2018).

    CAS  PubMed  Google Scholar 

  20. 20.

    Zacharias, E. Über den Nucleolus. Botan. Zeit. 43, 257 (1885).

    Google Scholar 

  21. 21.

    Walter, H. & Brooks, D. E. Phase separation in cytoplasm, due to macromolecular crowding, is the basis for microcompartmentation. FEBS Lett. 361, 135–139 (1995).

    CAS  PubMed  Google Scholar 

  22. 22.

    Banani, S. F., Lee, H. O., Hyman, A. A. & Rosen, M. K. Biomolecular condensates: organizers of cellular biochemistry. Nat. Rev. Mol. Cell Biol. 18, 285–298 (2017).

    CAS  PubMed  Google Scholar 

  23. 23.

    Altmeyer, M. et al. Liquid demixing of intrinsically disordered proteins is seeded by poly(ADP-ribose). Nat. Commun. 6, 8088 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Strom, A. R. et al. Phase separation drives heterochromatin domain formation. Nature 547, 241–245 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Larson, A. G. et al. Liquid droplet formation by HP1α suggests a role for phase separation in heterochromatin. Nature 547, 236–240 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Cerase, A., Armaos, A., Cid, F., Avner, P. & Tartaglia, G. G. Xist lncRNA forms silencing granules that induce heterochromatin formation and repressive complexes recruitment by phase separation. Preprint at bioRxiv https://www.biorxiv.org/content/10.1101/351015v1 (2018).

  27. 27.

    Brangwynne, C. P., Mitchison, T. J. & Hyman, A. A. Active liquid-like behavior of nucleoli determines their size and shape in Xenopus laevis oocytes. Proc. Natl Acad. Sci. USA 108, 4334–4339 (2011).

    CAS  PubMed  Google Scholar 

  28. 28.

    Sheu-Gruttadauria, J. & MacRae, I. J. Phase transitions in the assembly and function of human miRISC. Cell 173, 946–957 (2018).

    CAS  PubMed  Google Scholar 

  29. 29.

    Schmidt, H. B. & Gorlich, D. Nup98 FG domains from diverse species spontaneously phase-separate into particles with nuclear pore-like permselectivity. eLife 4, e04251 (2015).

    PubMed Central  Google Scholar 

  30. 30.

    Jiang, H. et al. Phase transition of spindle-associated protein regulate spindle apparatus assembly. Cell 163, 108–122 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Banjade, S. & Rosen, M. K. Phase transitions of multivalent proteins can promote clustering of membrane receptors. eLife 3, e04123 (2014).

    PubMed Central  Google Scholar 

  32. 32.

    Winton, M. J. et al. Disturbance of nuclear and cytoplasmic TAR DNA-binding protein (TDP-43) induces disease-like redistribution, sequestration, and aggregate formation. J. Biol. Chem. 283, 13302–13309 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Johnson, B. S. et al. TDP-43 is intrinsically aggregation-prone, and amyotrophic lateral sclerosis-linked mutations accelerate aggregation and increase toxicity. J. Biol. Chem. 284, 20329–20339 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Sun, Z. et al. Molecular determinants and genetic modifiers of aggregation and toxicity for the ALS disease protein FUS/TLS. PLOS Biol. 9, e1000614 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Kato, M. et al. Cell-free formation of RNA granules: low complexity sequence domains form dynamic fibers within hydrogels. Cell 149, 753–767 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Van Treeck, B. & Parker, R. Emerging roles for intermolecular RNA-RNA interactions in RNP assemblies. Cell 174, 791–802 (2018).

    PubMed  Google Scholar 

  37. 37.

    Leung, A. K. Poly(ADP-ribose): an organizer of cellular architecture. J. Cell Biol. 205, 613–619 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    McGurk, L. et al. Poly(ADP-ribose) prevents pathological phase separation of TDP-43 by promoting liquid demixing and stress granule localization. Mol. Cell 71, 703–717 (2018).

    CAS  PubMed  Google Scholar 

  39. 39.

    Patel, A. et al. ATP as a biological hydrotrope. Science 356, 753–756 (2017).

    CAS  PubMed  Google Scholar 

  40. 40.

    King, O. D., Gitler, A. D. & Shorter, J. The tip of the iceberg: RNA-binding proteins with prion-like domains in neurodegenerative disease. Brain Res. 1462, 61–80 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Lin, Y., Protter, D. S., Rosen, M. K. & Parker, R. Formation and maturation of phase-separated liquid droplets by RNA-binding proteins. Mol. Cell 60, 208–219 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Molliex, A. et al. Phase separation by low complexity domains promotes stress granule assembly and drives pathological fibrillization. Cell 163, 123–133 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Brangwynne, C. P., Tompa, P. & Pappu, R. V. Polymer physics of intracellular phase transitions. Nat. Phys. 11, 899 (2015).

    CAS  Google Scholar 

  44. 44.

    Wang, J. et al. A molecular grammar governing the driving forces for phase separation of prion-like RNA binding proteins. Cell 174, 688–699 (2018).

    CAS  PubMed  Google Scholar 

  45. 45.

    Conicella, A. E., Zerze, G. H., Mittal, J. & Fawzi, N. L. ALS mutations disrupt phase separation mediated by alpha-helical structure in the TDP-43 low-complexity C-terminal domain. Structure 24, 1537–1549 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Ryan, V. H. et al. Mechanistic view of hnRNPA2 low-complexity domain structure, interactions, and phase separation altered by mutation and arginine methylation. Mol. Cell 69, 465–479 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Nelson, R. et al. Structure of the cross-beta spine of amyloid-like fibrils. Nature 435, 773–778 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Hughes, M. P. et al. Atomic structures of low-complexity protein segments reveal kinked beta sheets that assemble networks. Science 359, 698–701 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Guenther, E. L. et al. Atomic structures of TDP-43 LCD segments and insights into reversible or pathogenic aggregation. Nat. Struct. Mol. Biol. 25, 463–471 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Jain, S. et al. ATPase-modulated stress granules contain a diverse proteome and substructure. Cell 164, 487–498 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Protter, D. S. & Parker, R. Principles and properties of stress granules. Trends Cell Biol. 26, 668–679 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Kosik, K. S. & Krichevsky, A. M. The message and the messenger: delivering RNA in neurons. Sci. STKE 2002, e16 (2002).

    Google Scholar 

  53. 53.

    Vogler, T. O. et al. TDP-43 and RNA form amyloid-like myo-granules in regenerating muscle. Nature 563, 508–513 (2018).

    CAS  PubMed  Google Scholar 

  54. 54.

    Neumann, M. et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314, 130–133 (2006).

    CAS  PubMed  Google Scholar 

  55. 55.

    Salajegheh, M. et al. Sarcoplasmic redistribution of nuclear TDP-43 in inclusion body myositis. Muscle Nerve 40, 19–31 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Weihl, C. C. et al. TDP-43 accumulation in inclusion body myopathy muscle suggests a common pathogenic mechanism with frontotemporal dementia. J. Neurol. Neurosurg. Psychiatry 79, 1186–1189 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Irwin, D. J. et al. Frontotemporal lobar degeneration: defining phenotypic diversity through personalized medicine. Acta Neuropathol. 129, 469–491 (2015).

    PubMed  Google Scholar 

  58. 58.

    Kanekura, K. et al. Poly-dipeptides encoded by the C9orf72 repeats block global protein translation. Hum. Mol. Genet. 25, 1803–1813 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Deshaies, J. E. et al. TDP-43 regulates the alternative splicing of hnRNP A1 to yield an aggregation-prone variant in amyotrophic lateral sclerosis. Brain 141, 1320–1333 (2018).

    PubMed  Google Scholar 

  60. 60.

    Deng, H. X. et al. FUS-immunoreactive inclusions are a common feature in sporadic and non-SOD1 familial amyotrophic lateral sclerosis. Ann. Neurol. 67, 739–748 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Dormann, D. et al. ALS-associated fused in sarcoma (FUS) mutations disrupt transportin-mediated nuclear import. EMBO J. 29, 2841–2857 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Lu, L. et al. Amyotrophic lateral sclerosis-linked mutant SOD1 sequesters Hu antigen R (HuR) and TIA-1-related protein (TIAR): implications for impaired post-transcriptional regulation of vascular endothelial growth factor. J. Biol. Chem. 284, 33989–33998 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Volkening, K., Leystra-Lantz, C., Yang, W., Jaffee, H. & Strong, M. J. TAR DNA binding protein of 43 kDa (TDP-43), 14-3-3 proteins and copper/zinc superoxide dismutase (SOD1) interact to modulate NFL mRNA stability. Implications for altered RNA processing in amyotrophic lateral sclerosis (ALS). Brain Res. 1305, 168–182 (2009).

    CAS  PubMed  Google Scholar 

  64. 64.

    Liu-Yesucevitz, L. et al. TAR DNA binding protein-43 (TDP-43) associates with stress granules: analysis of cultured cells and pathological brain tissue. PLOS ONE 5, e13250 (2010).

    PubMed  PubMed Central  Google Scholar 

  65. 65.

    Elden, A. C. et al. Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature 466, 1069–1075 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Deng, H. X. et al. Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature 477, 211–215 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Neumann, M. et al. A new subtype of frontotemporal lobar degeneration with FUS pathology. Brain 132, 2922–2931 (2009).

    PubMed  PubMed Central  Google Scholar 

  68. 68.

    Maruyama, H. et al. Mutations of optineurin in amyotrophic lateral sclerosis. Nature 465, 223–226 (2010).

    CAS  PubMed  Google Scholar 

  69. 69.

    Schroder, R. et al. Mutant valosin-containing protein causes a novel type of frontotemporal dementia. Ann. Neurol. 57, 457–461 (2005).

    PubMed  Google Scholar 

  70. 70.

    Wilson, A. C., Dugger, B. N., Dickson, D. W. & Wang, D. S. TDP-43 in aging and Alzheimer’s disease — a review. Int. J. Clin. Exp. Pathol. 4, 147–155 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Schwab, C., Arai, T., Hasegawa, M., Yu, S. & McGeer, P. L. Colocalization of transactivation-responsive DNA-binding protein 43 and huntingtin in inclusions of Huntington disease. J. Neuropathol. Exp. Neurol. 67, 1159–1165 (2008).

    PubMed  Google Scholar 

  72. 72.

    Uryu, K. et al. Concomitant TAR-DNA-binding protein 43 pathology is present in Alzheimer disease and corticobasal degeneration but not in other tauopathies. J. Neuropathol. Exp. Neurol. 67, 555–564 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73.

    Nakashima-Yasuda, H. et al. Co-morbidity of TDP-43 proteinopathy in Lewy body related diseases. Acta Neuropathol. 114, 221–229 (2007).

    CAS  PubMed  Google Scholar 

  74. 74.

    Lippa, C. F. et al. Transactive response DNA-binding protein 43 burden in familial Alzheimer disease and Down syndrome. Arch. Neurol. 66, 1483–1488 (2009).

    PubMed  PubMed Central  Google Scholar 

  75. 75.

    Chanson, J. B. et al. TDP43-positive intraneuronal inclusions in a patient with motor neuron disease and Parkinson’s disease. Neurodegener. Dis. 7, 260–264 (2010).

    PubMed  Google Scholar 

  76. 76.

    Gallego-Iradi, M. C. et al. Subcellular localization of matrin 3 containing mutations associated with ALS and distal myopathy. PLOS ONE 10, e0142144 (2015).

    PubMed  PubMed Central  Google Scholar 

  77. 77.

    Couthouis, J. et al. A yeast functional screen predicts new candidate ALS disease genes. Proc. Natl Acad. Sci. USA 108, 20881–20890 (2011).

    CAS  PubMed  Google Scholar 

  78. 78.

    Couthouis, J. et al. Evaluating the role of the FUS/TLS-related gene EWSR1 in amyotrophic lateral sclerosis. Hum. Mol. Genet. 21, 2899–2911 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Freibaum, B. D., Chitta, R. K., High, A. A. & Taylor, J. P. Global analysis of TDP-43 interacting proteins reveals strong association with RNA splicing and translation machinery. J. Proteome Res. 9, 1104–1120 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Andersen, J. S. et al. Directed proteomic analysis of the human nucleolus. Curr. Biol. 12, 1–11 (2002).

    Google Scholar 

  81. 81.

    Shelkovnikova, T. A., Robinson, H. K., Troakes, C., Ninkina, N. & Buchman, V. L. Compromised paraspeckle formation as a pathogenic factor in FUSopathies. Hum. Mol. Genet. 23, 2298–2312 (2014).

    CAS  PubMed  Google Scholar 

  82. 82.

    Rajgor, D., Hanley, J. G. & Shanahan, C. M. Identification of novel nesprin-1 binding partners and cytoplasmic matrin-3 in processing bodies. Mol. Biol. Cell 27, 3894–3902 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83.

    Yamazaki, T. et al. FUS-SMN protein interactions link the motor neuron diseases ALS and SMA. Cell Rep. 2, 799–806 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84.

    Wang, I. F., Reddy, N. M. & Shen, C. K. Higher order arrangement of the eukaryotic nuclear bodies. Proc. Natl Acad. Sci. USA 99, 13583–13588 (2002).

    CAS  PubMed  Google Scholar 

  85. 85.

    Ishihara, T. et al. Decreased number of Gemini of coiled bodies and U12 snRNA level in amyotrophic lateral sclerosis. Hum. Mol. Genet. 22, 4136–4147 (2013).

    CAS  PubMed  Google Scholar 

  86. 86.

    Murakami, T. et al. ALS/FTD mutation-induced phase transition of FUS liquid droplets and reversible hydrogels into irreversible hydrogels impairs RNP granule function. Neuron 88, 678–690 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87.

    Patel, A. et al. A liquid-to-solid phase transition of the ALS protein FUS accelerated by disease mutation. Cell 162, 1066–1077 (2015).

    CAS  PubMed  Google Scholar 

  88. 88.

    Guo, L. et al. Nuclear-import receptors reverse aberrant phase transitions of RNA-binding proteins with prion-like domains. Cell 173, 677–692 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89.

    Arnold, E. S. et al. 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. USA 110, E736–E745 (2013).

    CAS  PubMed  Google Scholar 

  90. 90.

    Kawahara, Y. & Mieda-Sato, A. TDP-43 promotes microRNA biogenesis as a component of the Drosha and Dicer complexes. Proc. Natl Acad. Sci. USA 109, 3347–3352 (2012).

    CAS  PubMed  Google Scholar 

  91. 91.

    Coyne, A. N. et al. Fragile X protein mitigates TDP-43 toxicity by remodeling RNA granules and restoring translation. Hum. Mol. Genet. 24, 6886–6898 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92.

    Alami, N. H. et al. Axonal transport of TDP-43 mRNA granules is impaired by ALS-causing mutations. Neuron 81, 536–543 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93.

    Wang, I. F., Wu, L. S., Chang, H. Y. & Shen, C. K. TDP-43, the signature protein of FTLD-U, is a neuronal activity-responsive factor. J. Neurochem. 105, 797–806 (2008).

    CAS  PubMed  Google Scholar 

  94. 94.

    Liao, Y.-C. et al. RNA granules hitchhike on lysosomes for long-distance transport, using annexin A11 as a molecular tether. Preprint at SSRN https://ssrn.com/abstract=3312723 (2019).

  95. 95.

    Kanai, Y., Dohmae, N. & Hirokawa, N. Kinesin transports RNA: isolation and characterization of an RNA-transporting granule. Neuron 43, 513–525 (2004).

    CAS  PubMed  Google Scholar 

  96. 96.

    Fujii, R. & Takumi, T. TLS facilitates transport of mRNA encoding an actin-stabilizing protein to dendritic spines. J. Cell Sci. 118, 5755–5765 (2005).

    CAS  PubMed  Google Scholar 

  97. 97.

    Lopez-Erauskin, J. et al. ALS/FTD-linked mutation in FUS suppresses intra-axonal protein synthesis and drives disease without nuclear loss-of-function of FUS. Neuron 100, 816–830 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98.

    Qamar, S. et al. FUS phase separation is modulated by a molecular chaperone and methylation of arginine cation-pi interactions. Cell 173, 720–734 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99.

    Buratti, E. & Baralle, F. E. Characterization and functional implications of the RNA binding properties of nuclear factor TDP-43, a novel splicing regulator of CFTR exon 9. J. Biol. Chem. 276, 36337–36343 (2001).

    CAS  PubMed  Google Scholar 

  100. 100.

    Hallier, M., Lerga, A., Barnache, S., Tavitian, A. & Moreau-Gachelin, F. The transcription factor Spi-1/PU.1 interacts with the potential splicing factor TLS. J. Biol. Chem. 273, 4838–4842 (1998).

    CAS  PubMed  Google Scholar 

  101. 101.

    Tollervey, J. R. et al. Characterizing the RNA targets and position-dependent splicing regulation by TDP-43. Nat. Neurosci. 14, 452–458 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102.

    Polymenidou, M. et al. Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43. Nat. Neurosci. 14, 459–468 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103.

    Lagier-Tourenne, C. et al. Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs. Nat. Neurosci. 15, 1488–1497 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104.

    Huelga, S. C. et al. Integrative genome-wide analysis reveals cooperative regulation of alternative splicing by hnRNP proteins. Cell Rep. 1, 167–178 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105.

    Strong, M. J. et al. TDP43 is a human low molecular weight neurofilament (hNFL) mRNA-binding protein. Mol. Cell Neurosci. 35, 320–327 (2007).

    CAS  PubMed  Google Scholar 

  106. 106.

    Costessi, L., Porro, F., Iaconcig, A. & Muro, A. F. TDP-43 regulates beta-adducin (Add2) transcript stability. RNA Biol. 11, 1280–1290 (2014).

    PubMed  Google Scholar 

  107. 107.

    Colombrita, C. et al. TDP-43 and FUS RNA-binding proteins bind distinct sets of cytoplasmic messenger RNAs and differently regulate their post-transcriptional fate in motoneuron-like cells. J. Biol. Chem. 287, 15635–15647 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108.

    Ling, J. P., Pletnikova, O., Troncoso, J. C. & Wong, P. C. TDP-43 repression of nonconserved cryptic exons is compromised in ALS-FTD. Science 349, 650–655 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109.

    Schwartz, J. C. et al. FUS binds the CTD of RNA polymerase II and regulates its phosphorylation at Ser2. Genes Dev. 26, 2690–2695 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110.

    Zhou, Y., Liu, S., Liu, G., Ozturk, A. & Hicks, G. G. ALS-associated FUS mutations result in compromised FUS alternative splicing and autoregulation. PLOS Genet. 9, e1003895 (2013).

    PubMed  PubMed Central  Google Scholar 

  111. 111.

    Guerrero, E. N. et al. TDP-43/FUS in motor neuron disease: complexity and challenges. Prog. Neurobiol. 145–146, 78–97 (2016).

    PubMed  PubMed Central  Google Scholar 

  112. 112.

    Velazquez-Perez, L. C., Rodriguez-Labrada, R. & Fernandez-Ruiz, J. Spinocerebellar ataxia type 2: clinicogenetic aspects, mechanistic insights, and management approaches. Front. Neurol. 8, 472 (2017).

    PubMed  PubMed Central  Google Scholar 

  113. 113.

    Becker, L. A. et al. Therapeutic reduction of ataxin-2 extends lifespan and reduces pathology in TDP-43 mice. Nature 544, 367–371 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. 114.

    Zhang, K. et al. Stress granule assembly disrupts nucleocytoplasmic transport. Cell 173, 958–971 (2018).

    CAS  PubMed  Google Scholar 

  115. 115.

    Lee, K. H. et al. C9orf72 dipeptide repeats impair the assembly, dynamics, and function of membrane-less organelles. Cell 167, 774–788 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 116.

    Bakthavachalu, B. et al. RNP-granule assembly via ataxin-2 disordered domains is required for long-term memory and neurodegeneration. Neuron 98, 754–766 (2018).

    CAS  PubMed  Google Scholar 

  117. 117.

    Nonhoff, U. et al. Ataxin-2 interacts with the DEAD/H-box RNA helicase DDX6 and interferes with P-bodies and stress granules. Mol. Biol. Cell 18, 1385–1396 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118.

    Johnson, J. O. et al. Exome sequencing reveals VCP mutations as a cause of familial ALS. Neuron 68, 857–864 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. 119.

    Fecto, F. et al. SQSTM1 mutations in familial and sporadic amyotrophic lateral sclerosis. Arch. Neurol. 68, 1440–1446 (2011).

    PubMed  Google Scholar 

  120. 120.

    Wu, C. H. et al. Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis. Nature 488, 499–503 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121.

    Nicolas, A. et al. Genome-wide analyses identify KIF5A as a novel ALS gene. Neuron 97, 1268–1283 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122.

    DeJesus-Hernandez, M. et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9orf72 causes chromosome 9p-linked FTD and ALS. Neuron 72, 245–256 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. 123.

    Renton, A. E. et al. A hexanucleotide repeat expansion in C9orf72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72, 257–268 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. 124.

    Freischmidt, A. et al. Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia. Nat. Neurosci. 18, 631–636 (2015).

    CAS  PubMed  Google Scholar 

  125. 125.

    Bannwarth, S. et al. A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement. Brain 137, 2329–2345 (2014).

    PubMed  PubMed Central  Google Scholar 

  126. 126.

    Smith, B. N. et al. Exome-wide rare variant analysis identifies TUBA4A mutations associated with familial ALS. Neuron 84, 324–331 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. 127.

    Puls, I. et al. Mutant dynactin in motor neuron disease. Nat. Genet. 33, 455–456 (2003).

    CAS  PubMed  Google Scholar 

  128. 128.

    Greenway, M. J. et al. ANG mutations segregate with familial and ‘sporadic’ amyotrophic lateral sclerosis. Nat. Genet. 38, 411–413 (2006).

    CAS  PubMed  Google Scholar 

  129. 129.

    Chen, Y. Z. et al. DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4). Am. J. Hum. Genet. 74, 1128–1135 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 130.

    Kaneb, H. M. et al. Deleterious mutations in the essential mRNA metabolism factor, hGle1, in amyotrophic lateral sclerosis. Hum. Mol. Genet. 24, 1363–1373 (2015).

    CAS  PubMed  Google Scholar 

  131. 131.

    Buchan, J. R., Kolaitis, R. M., Taylor, J. P. & Parker, R. Eukaryotic stress granules are cleared by autophagy and Cdc48/VCP function. Cell 153, 1461–1474 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 132.

    Matus, S., Bosco, D. A. & Hetz, C. Autophagy meets fused in sarcoma-positive stress granules. Neurobiol. Aging 35, 2832–2835 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 133.

    Dao, T. P. et al. Ubiquitin modulates liquid-liquid phase separation of UBQLN2 via disruption of multivalent interactions. Mol. Cell 69, 965–978 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. 134.

    Monahan, Z., Shewmaker, F. & Pandey, U. B. Stress granules at the intersection of autophagy and ALS. Brain Res. 1649, 189–200 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. 135.

    Thomas, M., Alegre-Abarrategui, J. & Wade-Martins, R. RNA dysfunction and aggrephagy at the centre of an amyotrophic lateral sclerosis/frontotemporal dementia disease continuum. Brain 136, 1345–1360 (2013).

    PubMed  Google Scholar 

  136. 136.

    Ash, P. E. et al. Unconventional translation of C9orf72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. Neuron 77, 639–646 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. 137.

    Mann, D. M. et al. Dipeptide repeat proteins are present in the p62 positive inclusions in patients with frontotemporal lobar degeneration and motor neurone disease associated with expansions in C9orf72. Acta Neuropathol. Commun. 1, 68 (2013).

    PubMed  PubMed Central  Google Scholar 

  138. 138.

    Mori, K. et al. hnRNP A3 binds to GGGGCC repeats and is a constituent of p62-positive/TDP43-negative inclusions in the hippocampus of patients with C9orf72 mutations. Acta Neuropathol. 125, 413–423 (2013).

    CAS  PubMed  Google Scholar 

  139. 139.

    Mori, K. et al. The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science 339, 1335–1338 (2013).

    CAS  PubMed  Google Scholar 

  140. 140.

    Schludi, M. H. et al. Distribution of dipeptide repeat proteins in cellular models and C9orf72 mutation cases suggests link to transcriptional silencing. Acta Neuropathol. 130, 537–555 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. 141.

    Zu, T. et al. Non-ATG-initiated translation directed by microsatellite expansions. Proc. Natl Acad. Sci. USA 108, 260–265 (2011).

    CAS  PubMed  Google Scholar 

  142. 142.

    Gendron, T. F. et al. Antisense transcripts of the expanded C9orf72 hexanucleotide repeat form nuclear RNA foci and undergo repeat-associated non-ATG translation in c9FTD/ALS. Acta Neuropathol. 126, 829–844 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. 143.

    Mackenzie, I. R. et al. Dipeptide repeat protein pathology in C9orf72 mutation cases: clinico-pathological correlations. Acta Neuropathol. 126, 859–879 (2013).

    CAS  PubMed  Google Scholar 

  144. 144.

    Zu, T. et al. RAN proteins and RNA foci from antisense transcripts in C9orf72 ALS and frontotemporal dementia. Proc. Natl Acad. Sci. USA 110, E4968–E4977 (2013).

    CAS  PubMed  Google Scholar 

  145. 145.

    Todd, P. K. et al. CGG repeat-associated translation mediates neurodegeneration in fragile X tremor ataxia syndrome. Neuron 78, 440–455 (2013).

    CAS  PubMed  Google Scholar 

  146. 146.

    Banez-Coronel, M. et al. RAN translation in Huntington disease. Neuron 88, 667–677 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. 147.

    Lin, Y. et al. Toxic PR poly-dipeptides encoded by the C9orf72 repeat expansion target LC domain polymers. Cell 167, 789–802 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. 148.

    Kwon, I. et al. Poly-dipeptides encoded by the C9orf72 repeats bind nucleoli, impede RNA biogenesis, and kill cells. Science 345, 1139–1145 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. 149.

    Wen, X. et al. Antisense proline-arginine RAN dipeptides linked to C9orf72-ALS/FTD form toxic nuclear aggregates that initiate in vitro and in vivo neuronal death. Neuron 84, 1213–1225 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. 150.

    Freibaum, B. D. et al. GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport. Nature 525, 129–133 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. 151.

    Mizielinska, S. et al. C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins. Science 345, 1192–1194 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. 152.

    Zhang, Y. J. et al. Poly(GR) impairs protein translation and stress granule dynamics in C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis. Nat. Med. 24, 1136–1142 (2018).

    CAS  PubMed  Google Scholar 

  153. 153.

    Prudencio, M. et al. Distinct brain transcriptome profiles in C9orf72-associated and sporadic ALS. Nat. Neurosci. 18, 1175–1182 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. 154.

    Jovicic, A. et al. Modifiers of C9orf72 dipeptide repeat toxicity connect nucleocytoplasmic transport defects to FTD/ALS. Nat. Neurosci. 18, 1226–1229 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. 155.

    Zhang, K. et al. The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature 525, 56–61 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. 156.

    Burguete, A. S. et al. GGGGCC microsatellite RNA is neuritically localized, induces branching defects, and perturbs transport granule function. eLife 4, e08881 (2015).

    PubMed  PubMed Central  Google Scholar 

  157. 157.

    Shi, K. Y. et al. Toxic PRn poly-dipeptides encoded by the C9orf72 repeat expansion block nuclear import and export. Proc. Natl Acad. Sci. USA 114, E1111–E1117 (2017).

    CAS  PubMed  Google Scholar 

  158. 158.

    Boeynaems, S. et al. Phase separation of C9orf72 dipeptide repeats perturbs stress granule dynamics. Mol. Cell 65, 1044–1055 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. 159.

    Taneja, K. L., McCurrach, M., Schalling, M., Housman, D. & Singer, R. H. Foci of trinucleotide repeat transcripts in nuclei of myotonic dystrophy cells and tissues. J. Cell Biol. 128, 995–1002 (1995).

    CAS  PubMed  Google Scholar 

  160. 160.

    Zhang, N. & Ashizawa, T. RNA toxicity and foci formation in microsatellite expansion diseases. Curr. Opin. Genet. Dev. 44, 17–29 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. 161.

    Maharana, S. et al. RNA buffers the phase separation behavior of prion-like RNA binding proteins. Science 360, 918–921 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. 162.

    Van Treeck, B. et al. RNA self-assembly contributes to stress granule formation and defining the stress granule transcriptome. Proc. Natl Acad. Sci. USA 115, 2734–2739 (2018).

    PubMed  Google Scholar 

  163. 163.

    Khong, A. et al. The stress granule transcriptome reveals principles of mRNA accumulation in stress granules. Mol. Cell 68, 808–820 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. 164.

    Jain, A. & Vale, R. D. RNA phase transitions in repeat expansion disorders. Nature 546, 243–247 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. 165.

    Lee, Y. B. et al. Hexanucleotide repeats in ALS/FTD form length-dependent RNA foci, sequester RNA binding proteins, and are neurotoxic. Cell Rep. 5, 1178–1186 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. 166.

    Wang, E. T. et al. Transcriptome-wide regulation of pre-mRNA splicing and mRNA localization by muscleblind proteins. Cell 150, 710–724 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. 167.

    Wojtkowiak-Szlachcic, A. et al. Short antisense-locked nucleic acids (all-LNAs) correct alternative splicing abnormalities in myotonic dystrophy. Nucleic Acids Res. 43, 3318–3331 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. 168.

    Fratta, P. et al. C9orf72 hexanucleotide repeat associated with amyotrophic lateral sclerosis and frontotemporal dementia forms RNA G-quadruplexes. Sci. Rep. 2, 1016 (2012).

    PubMed  PubMed Central  Google Scholar 

  169. 169.

    Haeusler, A. R. et al. C9orf72 nucleotide repeat structures initiate molecular cascades of disease. Nature 507, 195–200 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. 170.

    Sareen, D. et al. Targeting RNA foci in iPSC-derived motor neurons from ALS patients with a C9orf72 repeat expansion. Sci. Transl Med. 5, 208ra149 (2013).

    PubMed  PubMed Central  Google Scholar 

  171. 171.

    Donnelly, C. J. et al. RNA toxicity from the ALS/FTD C9orf72 expansion is mitigated by antisense intervention. Neuron 80, 415–428 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. 172.

    Xu, Z. et al. Expanded GGGGCC repeat RNA associated with amyotrophic lateral sclerosis and frontotemporal dementia causes neurodegeneration. Proc. Natl Acad. Sci. USA 110, 7778–7783 (2013).

    CAS  PubMed  Google Scholar 

  173. 173.

    Kim, H. J. & Taylor, J. P. Lost in transportation: nucleocytoplasmic transport defects in ALS and other neurodegenerative diseases. Neuron 96, 285–297 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. 174.

    Nousiainen, H. O. et al. Mutations in mRNA export mediator GLE1 result in a fetal motoneuron disease. Nat. Genet. 40, 155–157 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  175. 175.

    Gasset-Rosa, F. et al. Polyglutamine-expanded huntingtin exacerbates age-related disruption of nuclear integrity and nucleocytoplasmic transport. Neuron 94, 48–57 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. 176.

    Hernandez-Vega, A. et al. Local nucleation of microtubule bundles through tubulin concentration into a condensed tau phase. Cell Rep. 20, 2304–2312 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. 177.

    Wegmann, S. et al. Tau protein liquid-liquid phase separation can initiate tau aggregation. EMBO J. 37, e98049 (2018).

    PubMed  PubMed Central  Google Scholar 

  178. 178.

    Zhang, X. et al. RNA stores tau reversibly in complex coacervates. PLOS Biol. 15, e2002183 (2017).

    PubMed  PubMed Central  Google Scholar 

  179. 179.

    Ambadipudi, S., Biernat, J., Riedel, D., Mandelkow, E. & Zweckstetter, M. Liquid-liquid phase separation of the microtubule-binding repeats of the Alzheimer-related protein Tau. Nat. Commun. 8, 275 (2017).

    PubMed  PubMed Central  Google Scholar 

  180. 180.

    Ferreon, J. C. et al. Acetylation disfavors tau phase separation. Int. J. Mol. Sci. 19, E1360 (2018).

    PubMed  Google Scholar 

  181. 181.

    Kostylev, M. A. et al. Liquid and hydrogel phases of PrPC linked to conformation shifts and triggered by Alzheimer’s amyloid-beta oligomers. Mol. Cell 72, 426–443 (2018).

    CAS  PubMed  Google Scholar 

  182. 182.

    Anderson, P. & Kedersha, N. Stress granules: the Tao of RNA triage. Trends Biochem. Sci. 33, 141–150 (2008).

    CAS  PubMed  Google Scholar 

  183. 183.

    Decker, C. J. & Parker, R. P-Bodies and stress granules: possible roles in the control of translation and mRNA degradation. Cold Spring Harb. Perspect. Biol. 4, a012286 (2012).

    PubMed  PubMed Central  Google Scholar 

  184. 184.

    Ramaswami, M., Taylor, J. P. & Parker, R. Altered ribostasis: RNA-protein granules in degenerative disorders. Cell 154, 727–736 (2013).

    CAS  PubMed  Google Scholar 

  185. 185.

    Kedersha, N. et al. Stress granules and processing bodies are dynamically linked sites of mRNP remodeling. J. Cell Biol. 169, 871–884 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  186. 186.

    Hoyle, N. P., Castelli, L. M., Campbell, S. G., Holmes, L. E. & Ashe, M. P. 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 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  187. 187.

    Parker, R. & Sheth, U. P bodies and the control of mRNA translation and degradation. Mol. Cell 25, 635–646 (2007).

    CAS  Google Scholar 

  188. 188.

    Wilczynska, A., Aigueperse, C., Kress, M., Dautry, F. & Weil, D. The translational regulator CPEB1 provides a link between DCP1 bodies and stress granules. J. Cell Sci. 118, 981–992 (2005).

    CAS  PubMed  Google Scholar 

  189. 189.

    Mahboubi, H. & Stochaj, U. Nucleoli and stress granules: connecting distant relatives. Traffic 15, 1179–1193 (2014).

    CAS  PubMed  Google Scholar 

  190. 190.

    Trinkle-Mulcahy, L. & Sleeman, J. E. The Cajal body and the nucleolus: “in a relationship” or “it’s complicated”? RNA Biol. 14, 739–751 (2017).

    PubMed  Google Scholar 

  191. 191.

    Hofweber, M. et al. Phase separation of FUS is suppressed by its nuclear import receptor and arginine methylation. Cell 173, 706–719 (2018).

    CAS  PubMed  Google Scholar 

  192. 192.

    Wiltzius, J. J. et al. Molecular mechanisms for protein-encoded inheritance. Nat. Struct. Mol. Biol. 16, 973–978 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

J.P.T.’s research work is funded by the Howard Hughes Medical Institute and the St Jude Research Collaborative on the Biology of Membraneless Organelles.

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Nature Reviews Neurology thanks J. Rothstein and other anonymous reviewers for their contribution to the peer review of this work.

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Nedelsky, N.B., Taylor, J.P. Bridging biophysics and neurology: aberrant phase transitions in neurodegenerative disease. Nat Rev Neurol 15, 272–286 (2019). https://doi.org/10.1038/s41582-019-0157-5

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