percolation threshold and material properties
of specific condensates. Thus, one promising
approach to restoring material properties to
condensates is to target individual constituents
that are deemed druggable by conventional
criteria, with the desired effect of shifting the
percolation threshold and material properties
of a specific condensate in the desired direction.
For example, in the setting of ALS, there is evi-
dence of altered material properties and func-
tions of a variety of RNP granules, such as stress
granules and RNA transport granules. It has
been proposed that depletion of ataxin 2 ame-
liorates neurodegeneration in a mouse model of
ALS through precisely this mechanism, resulting
in decreased TDP-43 pathology ( 61 ). Another at-
tractive target to restore normal material proper-
ties in this way may be G3BP, which serves as a
more central node in the assembly of these
condensates. Indeed, knockdown or inhibition
of G3BP enhances local translation in neuronal
processes, protects against axonal injury, and
promotes axonal regeneration ( 62 ).
Beyond targeting the network of condensate
constituents to influence material properties,
an alternative approach might be to target
key pathological phase transitions themselves,
such as assembly of pathological TDP-43 or
FUS fibrils. In this strategy, one might exploit
the chaperones that specifically target these
assemblies. Specifically, it was recently shown
that nuclear import receptors (karyopherins)
function as chaperones for and can reverse
pathological phase transitions of their clients.
Indeed, the activity of KapB2 reverses patho-
logical phase transitions by proteins harbor-
ing the cognate PY-NLS (i.e., FUS, hnRNPA1,
hnRNPA2), whereas the activity of KapB1 to-
gether with importin-areverses pathological
phase transitions of TDP-43 in vitro and in vivo
( 63 ). Thus, strategies to augment the activity of
these chaperones may be beneficial in a dis-
ease setting. Related to this, VCP serves as an
important segregase in the dismantling of
stress granules and perhaps other conden-
sates. Indeed, it was recently shown that a small
molecule agonist of ULK1/2 kinases, which
phosphorylate and activate VCP, accelerates
stress granule disassembly ( 64 ). It is likely that
our improved understanding of the causes of
dynamical arrest, pathological liquid-to-solid
transitions, and the loss of heterotypic buffer-
ing will pave the way for targeting functional
restoration and regulation of condensates as
potent therapeutic strategies.REFERENCES AND NOTES- M. Katoet al.,Cell 149 , 753–767 (2012).
- Q. Cao, D. R. Boyer, M. R. Sawaya, P. Ge, D. S. Eisenberg,
Nat. Struct. Mol. Biol. 26 , 619–627 (2019). - B. Liet al.,Nat. Commun. 9 , 3609 (2018).
- M. Goedert, D. S. Eisenberg, R. A. Crowther,Annu. Rev. Neurosci.
40 , 189–210 (2017).
5. D. T. Murrayet al.,Cell 171 , 615–627.e16 (2017).
6. H. J. Kimet al.,Nature 495 , 467–473 (2013).
7. I. R. Mackenzieet al.,Neuron 95 , 808–816.e9 (2017).
8. A. Molliexet al.,Cell 163 , 123–133 (2015).
9. Y. Lin, D. S. Protter, M. K. Rosen, R. Parker,Mol. Cell 60 , 208–219 (2015).
10. A. Patelet al.,Cell 162 , 1066–1077 (2015).
11. T. Murakamiet al.,Neuron 88 , 678–690 (2015).
12. S. Wegmannet al.,EMBO J. 37 , e98049 (2018).
13. S. Rayet al.,Nat. Chem. 12 , 705–716 (2020).
14. J. Yang, X. Yang,Front. Genet. 11 , 754 (2020).
15. A. K. Buellet al.,Proc. Natl. Acad. Sci. U.S.A. 111 , 7671–7676 (2014).
16. A. E. Conicella, G. H. Zerze, J. Mittal, N. L. Fawzi,Structure 24 ,
1537 – 1549 (2016).
17. S. Qamaret al.,Cell 173 , 720–734.e15 (2018).
18. D. S. W. Protter, R. Parker,Trends Cell Biol. 26 , 668–679 (2016).
19. Y.R.Li,O.D.King,J.Shorter,A.D.Gitler,J. Cell Biol. 201 , 361–372 (2013).
20. N. H. Alamiet al.,Neuron 81 , 536–543 (2014).
21. R. Tanet al.,Nat. Cell Biol. 21 , 1078–1085 (2019).
22. J. Wanget al.,Cell 174 , 688–699.e16 (2018).
23. P. Yanget al.,Cell 181 , 325–345.e28 (2020).
24. S. F. Banani, H. O. Lee, A. A. Hyman, M. K. Rosen,Nat. Rev.
Mol. Cell Biol. 18 , 285–298 (2017).
25. Y. Shin, C. P. Brangwynne,Science 357 , eaaf4382 (2017).
26. L. J. Sweetlove, A. R. Fernie,Nat. Commun. 9 , 2136 (2018).
27. S. Janget al.,Neuron 90 , 278–291 (2016).
28. F. Wippichet al.,Cell 152 , 791–805 (2013).
29. D. M. Mitreaet al.,Nat. Commun. 9 , 842 (2018).
30. T. S. Harmon, A. S. Holehouse, M. K. Rosen, R. V. Pappu,eLife
6 , e30294 (2017).
31. S. L. McKnight,Trends Biochem. Sci. 44 , 899–901 (2019).
32. S. Boeynaemset al.,Proc. Natl. Acad. Sci. U.S.A. 116 , 7889–7898 (2019).
33. C. Fallini, G. J. Bassell, W. Rossoll,Hum. Mol. Genet. 21 ,
3703 – 3718 (2012).
34. J.P.Taylor,R.H.BrownJr.,D.W.Cleveland,Nature 539 , 197–206 (2016).
35. J. P. Ling, O. Pletnikova, J. C. Troncoso, P. C. Wong,Science
349 , 650–655 (2015).
36. C. Lagier-Tourenneet al.,Nat. Neurosci. 15 , 1488–1497 (2012).
37. H. Olzschaet al.,Cell 144 , 67–78 (2011).
38. J. Sreedharanet al.,Science 319 , 1668–1672 (2008).
39. T. J. Kwiatkowski Jr.et al.,Science 323 , 1205–1208 (2009).
40. C. Vanceet al.,Science 323 , 1208–1211 (2009).
41. Y. Leeet al.,J. Clin. Invest. 128 , 1164–1177 (2018).
42. A. Menschet al.,Exp. Neurol. 306 , 222–231 (2018).
43. A. C. Eldenet al.,Nature 466 , 1069–1075 (2010).
44. Y. C. Liaoet al.,Cell 179 , 147–164.e20 (2019).
45. N. B. Nedelsky, J. P. Taylor,Nat. Rev. Neurol. 15 , 272–286 (2019).
46. J. O. Johnsonet al.,Neuron 68 , 857–864 (2010).
47. G. D. Wattset al.,Nat. Genet. 36 , 377–381 (2004).
48. J.R.Buchan,R.M.Kolaitis,J.P.Taylor,R.Parker,Cell 153 , 1461–1474 (2013).
49. H. X. Denget al.,Nature 477 , 211–215 (2011).
50. E. J. Alexanderet al.,Proc. Natl. Acad. Sci. U.S.A. 115 , E11485–E11494 (2018).
51. H. Maruyamaet al.,Nature 465 , 223–226 (2010).
52. C. Pottieret al.,Acta Neuropathol. 130 , 77–92 (2015).
53. K. H. Leeet al.,Cell 167 , 774–788.e17 (2016).
54. K. Y. Shiet al.,Proc. Natl. Acad. Sci. U.S.A. 114 , E1111–E1117 (2017).
55. S. Boeynaemset al.,Mol. Cell 65 , 1044–1055.e5 (2017).
56. A. R. Haeusleret al.,Nature 507 , 195–200 (2014).
57. I. Kwonet al.,Science 345 , 1139–1145 (2014).
58. F. Frottinet al.,Science 365 , 342–347 (2019).
59. A. Jain, R. D. Vale,Nature 546 , 243–247 (2017).
60. L. J. Sznajder, M. S. Swanson,Int. J. Mol. Sci. 20 , 3365 (2019).
61. L. A. Beckeret al.,Nature 544 , 367–371 (2017).
62. P. K. Sahooet al.,Nat. Commun. 9 , 3358 (2018).
63. L. Guoet al.,Cell 173 , 677–692.e20 (2018).
64. B. Wanget al.,Mol. Cell 74 , 742–757.e8 (2019).
ACKNOWLEDGMENTS
We thank N. Nedelsky for editorial assistance and M. White for
assistance with Fig. 2. J.P.T. acknowledges helpful interactions with
R. Parker, M. Rosen, T. Mittag, and B. Seeley. R.V.P. acknowledges
helpful interactions with J.-M. Choi, F. Dar, M. Farag, A. Holehouse, and
K. Ruff.Funding:Supported by HHMI (C.M. and J.P.T.), NIH grants
R35NS097974 (J.P.T.) and 5R01NS056114 (R.V.P.), NSF grant
MCB1614766 (R.V.P.), and the St. Jude Children’s Research Hospital
Research Collaborative on Membraneless Organelles (J.P.T. and
R.V.P.). The content is solely the responsibility of the authors and does
not necessarily represent the official views of the NIH.Competing
interests:J.P.T. is a consultant for Nido Biosciences and Faze Medicines.
R.V.P. is a member of the scientific advisory board of DewpointX. This
work was not funded or influenced in any way by these affiliations.
10.1126/science.abb803260 2 OCTOBER 2020•VOL 370 ISSUE 6512 sciencemag.org SCIENCE
Rise in [ ] Reduction in [ ] Displaces Mutation in123 4Fig. 3. Disruption of the physiologically relevant interplay between homotypic and heterotypic
interaction can lead to pathological phase transitions.Within multicomponent condensates, homotypic
interactions are typically buffered by an abundance of heterotypic interactions. This buffering guards
against pathological homotypic interactions that may give rise to liquid-to-solid phase transition and fibril
formation. In this simplified example, two types of macromolecules are illustrated, each depicted with
two interacting domains (rectangles) connected by a spacer region (black line). Green macromolecules
can form homotypic interactions with other green macromolecules or heterotypic interactions with yellow
macromolecules. Yellow macromolecules can form heterotypic interactions with green macromolecules. Under
normal conditions (top), the concentration of yellow macromolecules is such that heterotypic interactions
buffer any homotypic interactions. Four scenarios are shown in which this buffering is disrupted: (1 and 2)
imbalances in the relative concentrations of condensate constituents, (3) competition for heterotypic interactions
by the presence of an additional molecule, and (4) pathological mutations that favor homotypic interactions.
In each case, excessive homotypic interactions can lead to the deposition of solid-like structures within
condensates if they escape protein quality control mechanisms.
NEURODEGENERATION