TIA1 has a toxic relationship with tau. Toxic to neurons, that is. In the November 20 Nature Neuroscience, researchers led by Benjamin Wolozin of Boston University reported that the RNA-binding protein has a penchant for tau oligomers, stabilizing them and slowing their transformation into neurofibrillary tangles. Halving the expression of TIA1 in tau-transgenic mice lessened synaptic deficits, protected neurons, preserved memory, and prolonged the animals’ lives. The findings place TIA1, and potentially other RNA-binding proteins, at the scene of tau-mediated neurodegeneration, and support the idea that oligomers, rather than tangles, are the most noxious form of tau.

  • In vitro, TIA1 stunts tau fibril growth, stabilizes tau oligomers.
  • In PS19 mice, the protein preferentially associates with oligomers.
  • Reducing TIA1 promoted tau tangles and reduced toxicity.

Wolozin presented the bulk of the findings at the Phase Transitions in Biology and Disease meeting held last May in Leuven, Belgium (May 2017 conference news). There, and in the paper, the researchers reported that TIA1, which facilitates the formation of membraneless organelles called stress granules, plays a hand in neuronal damage in PS19 mice. These animals overexpress the P301S mutant tau that causes frontotemporal dementia, and suffer losses in synapses and neurons by six months of age. However, PS19 animals with half as much TIA1 mustered normal numbers of hippocampal and cortical neurons even at nine months old. At that age the animals performed at wild-type levels on the Y-maze and novel-object-recognition tests, and they lived an average of two months longer than animals with both copies of TIA1. Curiously, TIA1-deficient animals benefitted despite having more neurofibrillary tangles in their brains than PS19 controls.  

TIA1 Trouble.

Compared with wild-type animals (top two rows), synapses (synaptophysin, red) and neurons (NeuN, green) took a hit in PS19 mice (third row). Halving TIA1 expression protected (bottom row). [Courtesy of Apicco et al., Nature Neuroscience 2017.]

The paper dives deeper into the biochemical relationship between TIA1 and tau. First author Daniel Apicco and colleagues reported that in PS19 mice, tau oligomers co-aggregate with TIA1, as well as other RNA-binding proteins. In animals deficient in TIA1, RNA-binding proteins associated less with tau oligomers, suggesting that TIA1 plays a pivotal role in initiating these interactions. Reducing TIA1 also delayed the appearance of phosphorylated tau in the hippocampus, but doubled the amount that eventually accumulated there. Notably, Apicco found that TIA1 stymied the growth of tau fibrils in vitro, yet promoted the formation of smaller oligomers. Electron microscopy revealed that fibrils were stunted when TIA was present, and showed TIA1 and tau closely associating.

How does all this help explain tau pathology? Wolozin proposed that under conditions of cellular stress, tau becomes phosphorylated shortly after it is made in the somatodendritic compartment and starts to oligomerize. Then, instead of travelling to axons to stabilize microtubules, this toxic form of tau associates with TIA1 and RNA in stress granules. This jibes with recent findings that tau undergoes liquid-liquid phase separation, and that both RNA and phosphorylation of tau promote this transition (Jul 2017 newsAug 2017 news). TIA1’s interaction with tau would then stabilize these damaging tau oligomers, he proposed.

Aaron Gitler of Stanford University in California was intrigued by the apparent influence of TIA1 on tau phosphorylation and oligomerization, and noted that the results were convincing. “A role for stress granules now extends to tauopathies, and TIA1 may represent a new therapeutic target,” he wrote to Alzforum.

Jose Abisambra of the University of Kentucky in Lexington agreed, pointing out that TIA1 could play a broad role in pathogenesis of other neurodegenerative diseases where liquid droplet abnormalities have been implicated, including amyotrophic lateral sclerosis and frontotemporal dementia. “The fact that knockdown, and not knockout, of TIA1 offered neuroprotection gives hope that chemical targeting of TIA1 could offer benefits to patients suffering from these devastating disorders without complete ablation of TIA1,” he wrote to Alzforum. —Jessica Shugart

Comments

  1. In this new paper, Wolozin and colleagues provide convincing evidence of neuron rescue in the hippocampus and cortices of P301S-tau transgenic mice, upon TIA1 reduction. Cognition and lifespan are also improved.

    The result that phosphorylated tau is initially decreased but later elevated is very intriguing and could provide important insight into the molecular mechanisms of tau toxicity and cellular defenses to this toxicity. The increase in fibrillar tau and decrease in oligomeric tau with TIA1 reduction is also an interesting result. This effect seems to be quite strong, and combined evidence from IHC, solubility fractioning, and the in vitro experiments are convincing.

    A role for stress granules now extends to tauopathies, and TIA1 may represent a new therapeutic target. 

  2. The Wolozin lab furthers the investigation of their original finding that tau complexes with TIA1-positive stress granules (Vanderweyde et al., 2016). In this extension, they show that knocking down TIA1 improves outcomes in P301S mice. The careful and thorough characterization of these effects in a novel mouse model lends credence to the importance of stress granule formation and their prevention in tau pathogenesis. Compared to P301SxTIA+/+, PS19 TIA1 knockdown mice (P301SxTIA1+/-) showed improved cognition, extended lifespan, reduced neuronal and synaptic loss, and decreased cytoplasmic stress granules.

    A striking mechanistic finding was that TIA1 knockdown shifted tau species from oligomeric to fibrillar conformations. A major implication of this finding is that TIA1-tau complexes could participate in protein synthesis by regulating RNA-ribosome stability. Formation of pathological stress granules, structures replete with RNA, ribosomes, and distinct RNA-binding proteins, could serve as centers of cell protection by sequestering RNA and reducing translation under stress. As described in 1989 by the Binder group (Papasozomenos, 1989), tau associates with ribosomes, but the consequences of this interaction were unknown; using in vitro models, our group showed that tau impaired ribosomal function (Meier et al., 2016). However, more mechanistic insight is sorely missing. The specific recruitment of TIA1 to a tau-containing stress granule coalesces a mechanism of RNA regulation that participates in disease.

    Hints of tau-RNA associations date back to 1975, when Bryan et al. demonstrated that RNA interferes with microtubule stabilization (Bryan et al., 1975). Nearly 20 years later, the Mandelkow groups solidified the impact of polyanions, and RNA in particular, with the formation of PHF1 fibrils (Kampers  et al., 1996). Apicco et al. coalesce these and other fundamental studies solidifying the emerging concept of a role for tau in RNA regulation. Yet this role is more complex than anticipated. For example, recent studies show that monomeric tau stabilizes cytoplasmic RNA while oligomeric tau conformers destroy RNA (Violet et al., 2015; Bou Samra et al., 2017). Whether stress granule dynamics contribute to this mechanism remains unknown. It would be exciting to find that TIA1 serves as a conduit for the regulation of tau monomer equilibrium, and this in turn governs RNA stability.

    Another implication of the shift between fibrillar and oligomeric tau pools as a consequence of TIA1 knockdown is that molecular chaperones and co-chaperones could be recruited to drive this process. Indeed, work from the Hutton, Petrucelli, and Dickey labs, among others, has demonstrated the crucial role of molecular chaperones in regulating tau aggregation dynamics (Petrucelli et al., 2004; Dickey et al., 2005). The oligomer-to-fibril balance could be a concerted response by which stress granules form and recruit chaperones to manage the equilibrium.

    The emergence of this field is moving at a fast pace, as it has for other diseases where liquid droplet abnormalities are evident (e.g. FTLD and ALS). While the findings presented by the Wolozin lab are unique to tau, targeted abrogation of TIA1 in other disease processes sharing similar mechanisms could be a promising therapeutic angle. The fact that knockdown and not knockout of TIA1 offered neuroprotection gives hope that chemical targeting of TIA1 could offer benefits to patients suffering from these devastating disorders without complete ablation of TIA1.

    As any thought-provoking study, the data nudges the field to answer deeper questions about this mechanism. For example, how are tau-TIA1 granules formed and are they reversible? What is the consequence of tau-TIA1 complex formation, and importantly, what impact does it have on translation? Are there other targetable stress granule proteins that modulate tau pathogenesis? Answering these questions will undoubtedly help the field leap forward into designing new therapeutic strategies and offer key understanding of the molecular mechanisms driving RNA translation. 

    References:

    . 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.

    . Tau protein immunoreactivity in dementia of the Alzheimer type: II. Electron microscopy and pathogenetic implications. Effects of fixation on the morphology of the Alzheimer's abnormal filaments. Lab Invest. 1989 Mar;60(3):375-89. PubMed.

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

    . Inhibition of tubulin assembly by RNA and other polyanions: evidence for a required protein. Proc Natl Acad Sci U S A. 1975 Sep;72(9):3570-4. PubMed.

    . RNA stimulates aggregation of microtubule-associated protein tau into Alzheimer-like paired helical filaments. FEBS Lett. 1996 Dec 16;399(3):344-9. PubMed.

    . Prefibrillar Tau oligomers alter the nucleic acid protective function of Tau in hippocampal neurons in vivo. Neurobiol Dis. 2015 Oct;82:540-51. Epub 2015 Sep 16 PubMed.

    . A role for Tau protein in maintaining ribosomal DNA stability and cytidine deaminase-deficient cell survival. Nat Commun. 2017 Sep 25;8(1):693. PubMed.

    . CHIP and Hsp70 regulate tau ubiquitination, degradation and aggregation. Hum Mol Genet. 2004 Apr 1;13(7):703-14. PubMed.

    . Development of a high throughput drug screening assay for the detection of changes in tau levels -- proof of concept with HSP90 inhibitors. Curr Alzheimer Res. 2005 Apr;2(2):231-8. PubMed.

  3. This is an interesting and intriguing study from the Wolozin group, which builds on their previous work showing that tau participates in stress granule assembly and that the persistence of stress granules can promote tau aggregation (Vanderweyde et al., 2016). In this current study, the authors crossed Tia1 knockout mice with P301S mutant tau transgenic animals and showed that haploinsufficiency of the RNA-binding protein TIA1 reduced stress granule formation, and protected against tau-medicated synapse loss and cognitive defects. Despite this neuroprotective role, TIA1 reduction remarkably accelerated tau phosphorylation and neurofibrillary tangle accumulation in the P301S tau transgenic animals. However, the authors reconcile this paradoxical finding by showing that the loss of TIA1 in these mice reduced levels of the more soluble and toxic oligomeric tau species. This shed light on a potential mechanism underlying the neuroprotective role of TIA1. To follow up this finding, the authors used in vitro assays to show that TIA1 directly inhibits tau fibrillization and, in exchange, increases tau oligomerization. This study is timely as recent evidence now indicates that tau alone can also undergo liquid-liquid phase separation (Ambadipudi et al., 2017; Zhang et al., 2017), analogous to RNA-binding proteins (e.g. TDP-43, FUS, and TIA1) that aggregate in neurodegenerative disease. Collectively, these studies begin to provide important mechanistic insight into how RNA-binding proteins may act to regulate tau aggregation properties in AD and other tauopathies.

    Notably, mass spectrometry based proteomic analysis of the “tau oligomer” cortical fractions showed enrichment for a number of RNA-binding proteins (i.e. DDX6 and PABP) in the P301S tau mice with normal TIA1 levels compared to the Tia1 haploinsufficient mice. This suggests that RNA-binding proteins act synergistically to promote tau oligomerization and toxicity. These results are particularly interesting in light of our own research, where we have shown that U1 small nuclear ribonucleoprotein 70 kDa (U1-70K) and other core components of the spliceosome complex associate with tau and neurofibrillary tangles in AD detergent-insoluble aggregates in human cases of AD (Bai et al., 2013; Hales et al., 2016). Thus, future studies that seek to assess how specific RNA-binding proteins impact tau aggregation in vivo will be critical in resolving tau pathophysiology.

    References:

    . 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.

    . Liquid-liquid phase separation of the microtubule-binding repeats of the Alzheimer-related protein Tau. Nat Commun. 2017 Aug 17;8(1):275. PubMed.

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

    . U1 small nuclear ribonucleoprotein complex and RNA splicing alterations in Alzheimer's disease. Proc Natl Acad Sci U S A. 2013 Oct 8;110(41):16562-7. PubMed.

    . Changes in the detergent-insoluble brain proteome linked to amyloid and tau in Alzheimer's Disease progression. Proteomics. 2016 Dec;16(23):3042-3053. PubMed.

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References

News Citations

  1. Protein Liquid-Liquid Phase Transitions: The Science Is About to Gel
  2. Tau Hooks Up with RNA to Form Droplets
  3. More Droplets of Tau

Research Models Citations

  1. Tau P301S (Line PS19)

Further Reading

Papers

  1. . Stress granules as crucibles of ALS pathogenesis. J Cell Biol. 2013 Apr 29;201(3):361-72. PubMed.
  2. . Dysregulation of RNA Binding Protein Aggregation in Neurodegenerative Disorders. Front Mol Neurosci. 2017;10:89. Epub 2017 Apr 4 PubMed.

Primary Papers

  1. . Reducing the RNA binding protein TIA1 protects against tau-mediated neurodegeneration in vivo. Nat Neurosci Nov. 20, 2017