. RNA stores tau reversibly in complex coacervates. PLoS Biol. 2017 Jul;15(7):e2002183. Epub 2017 Jul 6 PubMed.

Recommends

Please login to recommend the paper.

Comments

  1. This work, from the laboratories of Ken Kosik and Songi Han, provides important new insight into the biology of tau protein. The manuscript builds on a growing body of work that is revolutionizing our knowledge of how proteins in the cell interact. For a very long time, we have known that there are many, many proteins that exhibit “sticky,” intrinsically disordered regions. These regions were thought to be a “nuisance,” but our understanding of their role changed dramatically with publication of a manuscript coming from Mike Rosen’s laboratory (Li et al., 2012). This group showed that proteins with multiple intrinsically disordered regions associate in a manner leading to structures analogous to “lipid droplets,” in that they will phase-separate from aqueous solutions. This phase separation turns out to be a major way that the cell organizes its functions, and multiple well-known structures exist based on the biology of liquid-liquid phase separation (LLPS); these structures include the nucleolus and the nuclear pore (Feric et al., 2016; Zhu and Brangwynne, 2015). 

    RNA binding proteins turn out to be one of the major groups of proteins that exhibit the properties of LLPS (Ash et al., 2014; Gitler and Shorter, 2011; Banani et al., 2017; Feric et al., 2016). The phase separation gives rise to RNA granules, which function in the cell to control RNA transport, translation, degradation, and sequestration (Anderson and Kedersha, 2008). Sequestration occurs during stress, when the cell needs to focus RNA translation on protective/reparative transcripts, and sequesters unnecessary transcripts into structures termed stress granules (Panas et al., 2016). Several groups, including my own, extended this idea to the realm of neurodegenerative disease by showing that RNA-binding proteins that are associated with disease (such as TDP-43 and FUS) associate with stress granules, and that disease-linked mutations increase formation of stress granules (Bosco et al., 2010; Colombrita et al., 2009Liu-Yesucevitz et al., 2010). 

    My group demonstrated that tau pathology associates with RNA binding proteins (Vanderweyde et al., 2012). More recently, we demonstrated two surprising results. First, we showed that tau functions during stress to promote stress granule formation; secondly, that the association of tau with stress granules increases tau’s tendency to aggregate (Vanderweyde et al., 2016). In a related paper, Joe Abisambra’s team demonstrated that pathological tau associates with the ribosome and inhibits RNA translation, which is a predicted outcome of the stress granule/translational stress response (Meier et al., 2016). Based on this observation, we also demonstrated that reducing the RNA binding protein TIA1 inhibits tau pathophysiology.

    Enter the present manuscript. It shows that tau undergoes liquid-liquid phase separation in the presence of RNA, and at concentrations as low as 2 μM, which approaches the concentration of tau in the neuron. The group demonstrates the phenomenon of liquid-liquid phase separation using multiple independent approaches. Importantly, they also demonstrate that tRNA has a particularly strong affinity for tau, with a Kd=460 nM, although nonspecific RNA also stimulates tau LLPS. The type of tau structure that forms when associated with RNA depends on the ratio of RNA:tau. At low ratios, the association stimulates formation of oligomers, while at high ratios, the association stimulates larger complexes and more robust LLPS. The LLPS is also sensitive to other conditions, such as salt and temperature.

    This work complements our recent work demonstrating that tau regulates stress granule biology, and provides strong support for a new vision suggesting roles for LLPS, stress granule formation, and the translational stress response in the pathophysiology of tauopathy.

    References:

    . Stress granules: the Tao of RNA triage. Trends Biochem Sci. 2008 Mar;33(3):141-50. PubMed.

    . Pathological stress granules in Alzheimer's disease. Brain Res. 2014 Oct 10;1584:52-8. Epub 2014 Aug 7 PubMed.

    . Biomolecular condensates: organizers of cellular biochemistry. Nat Rev Mol Cell Biol. 2017 May;18(5):285-298. Epub 2017 Feb 22 PubMed.

    . Mutant FUS proteins that cause amyotrophic lateral sclerosis incorporate into stress granules. Hum Mol Genet. 2010 Nov 1;19(21):4160-75. Epub 2010 Aug 10 PubMed.

    . TDP-43 is recruited to stress granules in conditions of oxidative insult. J Neurochem. 2009 Nov;111(4):1051-61. Epub 2009 Sep 16 PubMed.

    . Coexisting Liquid Phases Underlie Nucleolar Subcompartments. Cell. 2016 Jun 16;165(7):1686-97. Epub 2016 May 19 PubMed.

    . RNA-binding proteins with prion-like domains in ALS and FTLD-U. Prion. 2011 Jul 1;5(3) PubMed.

    . Phase transitions in the assembly of multivalent signalling proteins. Nature. 2012 Mar 7;483(7389):336-40. PubMed.

    . Tar DNA binding protein-43 (TDP-43) associates with stress granules: analysis of cultured cells and pathological brain tissue. PLoS One. 2010;5(10):e13250. PubMed.

    . Pathological Tau Promotes Neuronal Damage by Impairing Ribosomal Function and Decreasing Protein Synthesis. J Neurosci. 2016 Jan 20;36(3):1001-7. PubMed.

    . Mechanistic insights into mammalian stress granule dynamics. J Cell Biol. 2016 Nov 7;215(3):313-323. PubMed.

    . Interaction of tau with the RNA-Binding Protein TIA1 Regulates tau Pathophysiology and Toxicity. Cell Rep. 2016 May 17;15(7):1455-66. Epub 2016 May 6 PubMed.

    . Contrasting pathology of the stress granule proteins TIA-1 and G3BP in tauopathies. J Neurosci. 2012 Jun 13;32(24):8270-83. PubMed.

    . Nuclear bodies: the emerging biophysics of nucleoplasmic phases. Curr Opin Cell Biol. 2015 Jun;34:23-30. Epub 2015 May 15 PubMed.

    View all comments by Benjamin Wolozin

Make a Comment

To make a comment you must login or register.

This paper appears in the following:

News

  1. Tau Hooks Up with RNA to Form Droplets