Mackenzie IR, Nicholson AM, Sarkar M, Messing J, Purice MD, Pottier C, Annu K, Baker M, Perkerson RB, Kurti A, Matchett BJ, Mittag T, Temirov J, Hsiung GR, Krieger C, Murray ME, Kato M, Fryer JD, Petrucelli L, Zinman L, Weintraub S, Mesulam M, Keith J, Zivkovic SA, Hirsch-Reinshagen V, Roos RP, Züchner S, Graff-Radford NR, Petersen RC, Caselli RJ, Wszolek ZK, Finger E, Lippa C, Lacomis D, Stewart H, Dickson DW, Kim HJ, Rogaeva E, Bigio E, Boylan KB, Taylor JP, Rademakers R. TIA1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Promote Phase Separation and Alter Stress Granule Dynamics. Neuron. 2017 Aug 16;95(4):808-816.e9. PubMed.

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  1. The article by Mackenzie et al. adds a new RNA-binding protein to the list of RNA-binding proteins that are linked to ALS and frontotemporal dementia. In one sense the article adds to the growing body of literature showing that dysfunction of RNA-binding proteins contributes to the pathophysiology of ALS. The mutations in TIA1 appear to fit a pattern seen over and over in which mutations in low-complexity domains alter the mobility of TIA1 in the phase-separated mode, and increase the tendency of TIA1 to undergo liquid-liquid phase separation. Previous studies with other proteins suggest that the phase-separated RNA-binding proteins exhibit a tendency to aggregate into insoluble amyloid fibrils. TIA1 also exhibits this tendency, which is increased by the disease causing mutations.

    The pathology that occurs in vivo is that associated with TDP-43 inclusions. Previously we demonstrated that TDP-43 co-associates with TIA1 in stress granules in cells and in vivo (Liu-Yesucevitz et al., 2010). The Mackenzie team was able to reproduce the evidence of TDP-43 co-localization in cells. They observed that mutations in TIA1 increase formation of TDP-43 stress granules and aggregated TDP-43. They were unable to reproduce the co-localization of TDP-43 with TIA1 in human tissues; this is unfortunate, but could represent weaknesses of TIA1 commercial antibodies. TIA1 detection is sensitive to fixation time and is hard to detect with fixation longer than 48 hours. However, the group also states that they did not observe evidence of TIA1 aggregation by biochemistry, which would be an observation that would be largely independent of the quality of the antibodies.

    In another sense, the article presents a surprising finding because the group presents that the mutations increase the tendency of TIA1 to aggregate, and increase the tendency of the associated pathological protein, TDP-43, to aggregate, but presents no evidence that TIA1 is aggregating in vivo, nor any evidence that TIA1 co-localizes with TDP-43 or any other pathology in vivo. This contrasts with prior work by Hackman and colleagues showing that a different mutation in TIA1 causes a myopathy and formation of TIA1 aggregates (Hackman et al., 2013). This raises two possibilities: 1) TIA1 is inducing TDP-43 aggregation through an indirect mechanism, or 2) the right conditions for modeling and detecting the mechanisms of TIA1 aggregation have yet to be identified.

    TIA1 is one of the core nucleating RNA-binding proteins. My laboratory originally started studying TIA1 because we surveyed other core nucleating RNA-binding proteins (e.g., TIA1, TTP, G3BP1 with comparison to RNA-binding proteins such as DCP1, which are found in P-bodies) and observed that TIA1 elicited the strongest response for TDP-43 and later for tau protein (Liu-Yesucevitz et al., 2010; Vanderweyde et al., 2016; Vanderweyde et al., 2012). The current study provides some genetic validation for the hypothesized connection between TDP-43 and TIA1, but also raises many questions. For the moment, the most parsimonious conclusion is that the genetic link of TIA1 to ALS demonstrates its likely role in the biology of ALS, but has yet to identify the mechanism underlying the role.

    References:

    Liu-Yesucevitz L, Bilgutay A, Zhang YJ, Vanderweyde T, Vanderwyde T, Citro A, Mehta T, Zaarur N, McKee A, Bowser R, Sherman M, Petrucelli L, Wolozin B. 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.

    Hackman P, Sarparanta J, Lehtinen S, Vihola A, Evilä A, Jonson PH, Luque H, Kere J, Screen M, Chinnery PF, Åhlberg G, Edström L, Udd B. Welander distal myopathy is caused by a mutation in the RNA-binding protein TIA1. Ann Neurol. 2013 Apr;73(4):500-9. Epub 2013 Feb 11 PubMed.

    Vanderweyde T, Apicco DJ, Youmans-Kidder K, Ash PE, Cook C, Lummertz da Rocha E, Jansen-West K, Frame AA, Citro A, Leszyk JD, Ivanov P, Abisambra JF, Steffen M, Li H, Petrucelli L, Wolozin B. Interaction of tau with the RNA-Binding Protein TIA1 Regulates tau Pathophysiology and Toxicity. Cell Rep. 2016 May 17;15(7):1455-1466. Epub 2016 May 6 PubMed.

    Vanderweyde T, Yu H, Varnum M, Liu-Yesucevitz L, Citro A, Ikezu T, Duff K, Wolozin B. Contrasting pathology of the stress granule proteins TIA-1 and G3BP in tauopathies. J Neurosci. 2012 Jun 13;32(24):8270-83. PubMed.

    View all comments by Benjamin Wolozin

  2. This is a very nice paper with clear experimental evidence that TIA-1 mutant proteins have reduced mobility, and alter stress granule disassembly. The finding that TIA-1 mutations alter stress granule disassembly reaffirms the idea that maintaining correct stress granule dynamics is a key consideration in ALS therapy development. The added finding that the delayed disassembly of stress granules may contribute to the formation of distinct TDP-43 cytoplasmic inclusions is intriguing, and may offer a mechanism for how these inclusions arise. Moreover, it is reasonable to consider a potential feed forward amplification loop, such that as cytoplasmic accumulation proceeds, accompanied by eventual nuclear depletion of TDP-43, there will be a subsequent loss of G3BP1, which further compromises stress granule dynamics.

    View all comments by Christine Vande Velde

  3. Mackenzie, Rademakers, and colleagues have uncovered a new ALS-associated gene: TIA1. TIA1 is an RNA-binding protein that is a key component of stress granules, which are liquid-like membraneless organelles that form during cellular stress. A number of other stress granule proteins, such as TDP-43, have also been associated with ALS. TDP-43 forms pathological aggregates in 97 percent of ALS patients. Researchers hypothesize that RNA-binding proteins concentrating within liquid-like stress granules can nucleate insoluble, solid-like TDP-43 aggregates seen in disease. In line with this hypothesis, Mackenzie and colleagues find that ALS-associated mutations in TIA1 impair stress granule dissociation. Additionally, the authors demonstrate TDP-43 within stress granules is quite immobile and insoluble compared to typical stress granule proteins, which are highly motile and easily dissociate.

    One of the most interesting findings of the paper is that ALS-associated mutations in TIA1 also promote phase separation of TIA1 in vitro. ALS-associated mutations in other RNA-binding proteins promote the transition from a liquid droplet state to a solid, fibril state. Mutations in TIA1 seem to affect an earlier step in this sequence by facilitating phase separation, in addition to impairing the dynamic properties of the liquid droplets and promoting the formation of fibrils. This difference in mechanism might explain why TIA1 mutation carriers have somewhat unique TDP-43 pathology compared to other ALS patients. This paper provides further evidence that stress granules dynamics are important in the ALS disease cascade and likely will be an effective therapeutic target. 

    View all comments by Lindsay Becker

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