Two proteins involved in amyotrophic lateral sclerosis (ALS) precipitate formation of cellular granules by condensing into liquid droplets, according to recent studies. One, called hnRNPA1, forms transient stress granules by a process known as liquid-liquid demixing, report co-senior authors Paul Taylor and Tanja Mittag at St. Jude Children’s Research Hospital in Memphis, Tennessee, in the September 24 Cell. In other words, when a sufficient number of hnRNPA1 molecules condense together, they form a drop of liquid distinct from the surrounding cytosol. A better-known ALS protein, FUS, self-coalesces into liquid organelles that interact with RNA polymerase, report senior author Nicolas Fawzi and colleagues in the October 15 Molecular Cell. Fawzi and co-authors at Brown University in Providence, Rhode Island, also found that the structure of liquid FUS remains amorphous after condensation.

Both FUS and hnRNPA1 contain low-complexity domains, stretches of sticky amino acids that can mediate aggregation. Each research group was struck by the propensity of pure FUS or hnRNPA1 to condense into liquid droplets. In Cell, first author Amandine Molliex and colleagues report that hnRNPA1 also turns liquid inside cells. A disease-linked hnRNPA1 mutation also assembled into droplets.

Phase Separation and Fibrilization. Liquid-liquid phase separations (LLPS) of RNA binding proteins (RBPs) may create ideal conditions for fibrilization. Other proteins of low complexity might behave similarly. [Courtesy of Cell.]

From these droplets, both wild-type and mutant hnRNPA1 solidified into fibrils, though the mutant did so at a faster rate. The authors posit that a small amount of fibrils might have some beneficial function, such as stabilizing the granules while the cell needs them, but too many fibrils could become pathological.

Scientists earlier determined that FUS, too, promotes liquid formation (see Sep 2015 news), which is supported by the new findings reported in Molecular Cell. First author Kathleen Burke and colleagues used nuclear magnetic resonance spectroscopy to determine the three-dimensional position of individual residues in the FUS low-complexity domain. This region, which assumes no stable secondary structure, seems essential for FUS to condense into a liquid. When monomeric in solution, the region flapped loose, with little in the way of ordered conformation. Once FUS condensed in vitro, the low-complexity domain remained disordered, despite being more viscous. That implies the droplets were indeed liquid. They were not rigid structures such as aggregates or gels, which are solidified protein conglomerations long implicated in neurodegeneration.

FUS normally localizes to sites of transcription, so the authors examined the interaction between FUS liquid drops and RNA polymerase II. The carboxyl-terminal domain of that enzyme was able to nucleate FUS condensation and attached itself to the droplets, hinting that transcription occurs there.

To learn about the liquid and solid phases of proteins, and how they might figure in neurodegeneration, tune in to the Alzforum Webinar on October 30 at 11 a.m. U.S. Eastern time.—Amber Dance


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News Citations

  1. ALS Protein Said to Liquefy, Then Freeze en Route to Disease

Webinar Citations

  1. Fluid Business: Could “Liquid” Protein Herald Neurodegeneration?

Further Reading


  1. . Inverse size scaling of the nucleolus by a concentration-dependent phase transition. Curr Biol. 2015 Mar 2;25(5):641-6. Epub 2015 Feb 19 PubMed.
  2. . RNA transcription modulates phase transition-driven nuclear body assembly. Proc Natl Acad Sci U S A. 2015 Sep 22;112(38):E5237-45. Epub 2015 Sep 8 PubMed.
  3. . Stress granule assembly is mediated by prion-like aggregation of TIA-1. Mol Biol Cell. 2004 Dec;15(12):5383-98. Epub 2004 Sep 15 PubMed.
  4. . Edc3p and a glutamine/asparagine-rich domain of Lsm4p function in processing body assembly in Saccharomyces cerevisiae. J Cell Biol. 2007 Nov 5;179(3):437-49. PubMed.
  5. . Germline P granules are liquid droplets that localize by controlled dissolution/condensation. Science. 2009 Jun 26;324(5935):1729-32. Epub 2009 May 21 PubMed.

Primary Papers

  1. . Phase separation by low complexity domains promotes stress granule assembly and drives pathological fibrillization. Cell. 2015 Sep 24;163(1):123-33. PubMed.
  2. . Residue-by-Residue View of In Vitro FUS Granules that Bind the C-Terminal Domain of RNA Polymerase II. Mol Cell. 2015 Oct 15;60(2):231-41. Epub 2015 Oct 8 PubMed.