2018/7/5 Stress Granule Protein Stabilizes Tau Oligomers, Hastens Neurodegeneration | ALZFORUM

Stress Granule Protein Stabilizes Tau

Oligomers, Hastens Neurodegeneration
22 Nov 2017
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 neuro ibrillary tangles. Halving the expression of TIA1 in tau-transgenic
mice lessened synaptic de icits, protected neurons, preserved memory, and prolonged the
animals’ lives. The indings 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 ibril 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 indings 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-de icient animals bene itted despite having more
neuro ibrillary tangles in their brains than PS19 controls.

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 de icient 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 ibrils in vitro, yet promoted the formation of
smaller oligomers. Electron microscopy revealed that ibrils were stunted when TIA was
present, and showed TIA1 and tau closely associating.

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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 indings that tau
undergoes liquid-liquid
phase separation, and that
both RNA and TIA1 Trouble.
phosphorylation of tau
Compared with wild-type animals (top two rows), synapses
promote this transition (Jul
(synaptophysin, red) and neurons (NeuN, green) took a hit in PS19
2017 news; Aug 2017 news).
mice (third row). Halving TIA1 expression protected (bottom row).
TIA1’s interaction with tau
[Courtesy of Apicco et al., Nature Neuroscience 2017.]
would then stabilize these
damaging tau oligomers, he proposed.

Aaron Gitler of Stanford University in California was intrigued by the apparent in luence 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 bene its to patients
suffering from these devastating disorders without complete ablation of TIA1,” he wrote to
Alzforum. —Jessica Shugart

COMMENTS
Aaron Gitler
Stanford University

Posted: 22 Nov 2017

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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 ibrillar 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.

Joe Abisambra
University of Kentucky

Posted: 22 Nov 2017

The Wolozin lab furthers the investigation of their original inding 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 inding was that TIA1 knockdown shifted tau species from oligomeric to
ibrillar conformations. A major implication of this inding 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 speci ic 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 solidi ied the impact of polyanions, and RNA in particular, with the
formation of PHF1 ibrils (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.,

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2015; Bou Samra et al., 2017). Whether stress granule dynamics contribute to this mechanism
remains unknown. It would be exciting to ind 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 ibrillar 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- ibril balance could be a concerted
response by which stress granules form and recruit chaperones to manage the equilibrium.

The emergence of this ield 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 indings 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
bene its to patients suffering from these devastating disorders without complete ablation of
TIA1.

As any thought-provoking study, the data nudges the ield 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 ield leap forward into
designing new therapeutic strategies and offer key understanding of the molecular
mechanisms driving RNA translation.

References:
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):1455-66. Epub 2016 May 6
PubMed.

Papasozomenos SC. Tau protein immunoreactivity in dementia of the Alzheimer type:

II. Electron microscopy and pathogenetic implications. Effects of ixation on the
morphology of the Alzheimer's abnormal ilaments. Lab Invest. 1989 Mar;60(3):375-89.
PubMed.

Meier S, Bell M, Lyons DN, Rodriguez-Rivera J, Ingram A, Fontaine SN, Mechas E, Chen J, Wolozin
B, LeVine H 3rd, Zhu H, Abisambra JF. Pathological Tau Promotes Neuronal Damage by
Impairing Ribosomal Function and Decreasing Protein Synthesis. J Neurosci. 2016 Jan
20;36(3):1001-7. PubMed.

Bryan JB, Nagle BW, Doenges KH. 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.

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Kampers T, Friedhoff P, Biernat J, Mandelkow EM, Mandelkow E. RNA stimulates

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

Violet M, Chauderlier A, Delattre L, Tardivel M, Chouala MS, Sultan A, Marciniak E, Humez S,

Binder L, Kayed R, Lefebvre B, Bonnefoy E, Bué e L, Galas MC. Pre ibrillar 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.

Bou Samra E, Buhagiar-Labarchè de G, Machon C, Guitton J, Onclercq-Delic R, Green MR, Alibert

O, Gazin C, Veaute X, Amor-Gué ret M. A role for Tau protein in maintaining ribosomal
DNA stability and cytidine deaminase-de icient cell survival. Nat Commun. 2017 Sep
25;8(1):693. PubMed.

Petrucelli L, Dickson D, Kehoe K, Taylor J, Snyder H, Grover A, De Lucia M, McGowan E, Lewis J,

Prihar G, Kim J, Dillmann WH, Browne SE, Hall A, Voellmy R, Tsuboi Y, Dawson TM, Wolozin B,
Hardy J, Hutton M. CHIP and Hsp70 regulate tau ubiquitination, degradation and
aggregation. Hum Mol Genet. 2004 Apr 1;13(7):703-14. PubMed.

Dickey CA, Eriksen J, Kamal A, Burrows F, Kasibhatla S, Eckman CB, Hutton M, Petrucelli L.
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.

Nicholas Seyfried
Emory University

Posted: 27 Nov 2017

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 haploinsuf iciency 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 neuro ibrillary tangle accumulation in the P301S tau transgenic animals. However, the
authors reconcile this paradoxical inding 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 inding, the
authors used in vitro assays to show that TIA1 directly inhibits tau ibrillization 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.

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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 haploinsuf icient 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 neuro ibrillary 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 speci ic RNA-binding proteins impact tau aggregation in vivo will be critical
in resolving tau pathophysiology.

References:
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):1455-66. Epub 2016 May 6
PubMed.

Ambadipudi S, Biernat J, Riedel D, Mandelkow E, Zweckstetter M. Liquid-liquid phase

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

Zhang X, Lin Y, Eschmann NA, Zhou H, Rauch JN, Hernandez I, Guzman E, Kosik KS, Han S. RNA
stores tau reversibly in complex coacervates. PLoS Biol. 2017 Jul;15(7):e2002183. Epub
2017 Jul 6 PubMed.

Bai B, Hales CM, Chen PC, Gozal Y, Dammer EB, Fritz JJ, Wang X, Xia Q, Duong DM, Street C,
Cantero G, Cheng D, Jones DR, Wu Z, Li Y, Diner I, Heilman CJ, Rees HD, Wu H, Lin L, Szulwach
KE, Gearing M, Mufson EJ, Bennett DA, Montine TJ, Seyfried NT, Wingo TS, Sun YE, Jin P, Hanfelt
J, Willcock DM, Levey A, Lah JJ, Peng J. 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.

Hales CM, Dammer EB, Deng Q, Duong DM, Gearing M, Troncoso JC, Thambisetty M, Lah JJ,
Shulman JM, Levey AI, Seyfried NT. 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

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2018/7/5 Stress Granule Protein Stabilizes Tau Oligomers, Hastens Neurodegeneration | ALZFORUM

Protein Liquid-Liquid Phase Transitions: Tau Hooks Up with RNA to Form Droplets
The Science Is About to Gel 31 May 2017 19 Jul 2017

More Droplets of Tau 18 Aug 2017

Research Models Citations

Tau P301S (Line PS19)

FURTHER READING
Papers

Li YR, King OD, Shorter J, Gitler AD.
Stress granules as crucibles of ALS
pathogenesis. J Cell Biol. 2013 Apr
29;201(3):361-72. PubMed.
Maziuk B, Ballance HI, Wolozin B.
Dysregulation of RNA Binding Protein
Aggregation in Neurodegenerative
Disorders. Front Mol Neurosci.
2017;10:89. Epub 2017 Apr 4 PubMed.

PRIMARY PAPERS
Apicco DJ, Ash PE, Maziuk B, LeBlang C, Medalla M, Al Abdullatif A, Ferragud A, Botelho E,
Ballance HI, Dhawan U, Boudeau S, Cruz AL, Kashy D, Wong A, Goldberg LR, Yazdani N, Zhang C,
Ung CY, Tripodis Y, Kanaan NM, Ikezu T, Cottone P, Leszyk J, Li H, Luebke J, Bryant CD, Wolozin B.
Reducing the RNA binding protein TIA1 protects against tau-mediated neurodegeneration in
vivo. Nat Neurosci. 2018 Jan;21(1):72-80. Epub 2017 Nov 20 PubMed.

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