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Reducing the RNA binding protein TIA1 protects against tau-mediated neurodegeneration in vivo

Abstract

Emerging studies suggest a role for tau in regulating the biology of RNA binding proteins (RBPs). We now show that reducing the RBP T-cell intracellular antigen 1 (TIA1) in vivo protects against neurodegeneration and prolongs survival in transgenic P301S Tau mice. Biochemical fractionation shows co-enrichment and co-localization of tau oligomers and RBPs in transgenic P301S Tau mice. Reducing TIA1 decreased the number and size of granules co-localizing with stress granule markers. Decreasing TIA1 also inhibited the accumulation of tau oligomers at the expense of increasing neurofibrillary tangles. Despite the increase in neurofibrillary tangles, TIA1 reduction increased neuronal survival and rescued behavioral deficits and lifespan. These data provide in vivo evidence that TIA1 plays a key role in mediating toxicity and further suggest that RBPs direct the pathway of tau aggregation and the resulting neurodegeneration. We propose a model in which dysfunction of the translational stress response leads to tau-mediated pathology.

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Fig. 1: TIA1 reduction decreases cytoplasmic stress granules in PS19 mice while increasing nuclear TIA1.
Fig. 2: TIA1 reduction rescues synaptic and axonal loss in PS19 mice.
Fig. 3: TIA1 reduction protects against neurodegeneration in PS19 mice.
Fig. 4: TIA1 reduction improves memory and prolongs lifespan in PS19 mice.
Fig. 5: TIA1 reduction leads to an age-dependent increase in tau phosphorylation.
Fig. 6: TIA1 reduction shifts the biochemical and structural properties of tau aggregation.
Fig. 7: TIA1 inhibits tau fibrillization while increasing tau oligomerization.

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Acknowledgements

We thank P. Davies (Feinstein Institute) for provision of CP13 and PHF1 antibodies. We thank the following funding agencies for their support: B.W. received support from the NIH (AG050471, NS089544 and ES020395), BrightFocus Foundation, Alzheimer Association, Cure Alzheimer’s Fund and the Thome Medical Foundation; U.D. received support from a UGC-Raman Fellowship and the Government of India; T.I. received support from the NIH (R01 AG054199); H.L. received support from the Paul F. Glenn Foundation.

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Authors

Contributions

D.J.A. conceived, performed and analyzed experiments and wrote the original draft; P.E.A.A. performed and analyzed experiments; B.M., C.L., M.M., A.A.A., E.B., H.B., D.K., A.W., L.R.G., N.Y. and J. Leszyk performed experiments; A.F.F., C.Z., C.Y.U., N.M.K., T.I., P.C., J. Luebke, H.L. and C.B. provided expertise and edited the manuscript; and B.W. conceived, analyzed, wrote the original draft, edited, supervised and provided funding for the project.

Corresponding author

Correspondence to Benjamin Wolozin.

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B.W. is co-founder and Chief Scientific Officer for Aquinnah Pharmaceuticals Inc.

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Integrated supplementary information

Supplementary Figure 1 TIA1 reduction decreases cytoplasmic TIA1 granules in PS19 mice

A. IHC of cytoplasmic TIA1 granules (green, arrows) and DAPI (blue) in 6 month P301S Tia1+/+ and P301S Tia1+/- hippocampus (CA3). Scale bar = 5 |am. B. Quantification of number of TIA1 granules per cell in A. *p = 0.0394 (WT Tau Tia1+/+ vs WT Tau Tia1+/-) and *p = 0.0270 (P301S Tia1+/+ vs P301S Tia1+/-) by unpaired Student's T-test (one-tailed; n=4 mice/group, at least 20 cells imaged per mouse).

Supplementary Figure 2 TIA1 reduction protects against presynaptic and axonal degeneration up to 9 months of age in P301S Tau mice

A. IHC of NeuN (blue), synaptophysin (SYP, green), and neurofilament (NFL, red) in 9 month non-transgenic (WT Tau), PS19 (P301S Tau) and PS19 (P301S Tau) Tia1+/- hippocampus (CA3). Scale bar = 20 urn. B-C. Quantification of total SYP (B) and NFL (C) immunofluorescence in P301S Tia1+/+ and P301S Tia1+/- mice in A. SYP, unpaired Student's T-test (two-tailed) of P301S Tia1+/+ vs P301S Tia1+/-, *p=0.0491, N=10-13/group. NFL, unpaired Student's T-test (two-tailed) of P301S Tia1+/+ vs P301S Tia1+/-, *p=0.0441, N=11-12/group. Error bars denote means ± SEM normalized to wildtype levels equal to 1.

Supplementary Figure 3 TIA1 reduction increases tau binding to microtubules

A. Microtubule (MT)-bound and unbound fractions of P301S Tia1+/+ and P301S Tia1+/- cortex were separated by ultracentrifugation in RAB buffer. MT-bound (pellet, P) and MT-unbound (supernatant, S) fractions were immunoblotted for Tau13 (detects total human tau, top panels) and a-tubulin (bottom panel) to confirm efficient separation of MT elements in the S and P fractions. Top and middle panels represent longer and shorter exposure times of Tau13 immunoblot, respectively.

Supplementary Figure 4 TIA1 reduction protects against tau mediated neurodegeneration in the lateral entorhinal cortex

A. Quantification of the number of Nissl-positive neurons per field in layer II/III LEnt of 9 month non-transgenic (WT Tau) and PS19 (P301S Tau) mice. *p<0.05 by 2-way between-subjects ANOVA with Tukey's post-hoc tests (n=6/group). B. Quantification of average layer II/III cortical thickness in 9 month LEnt. **p=0.0095 ***p<0.001 by 2-way between-subjects ANOVA with Tukey's post-hoc tests (n=8 or more per/group). Error bars represent means ± SEM.

Supplementary Figure 5 PS19 mice exhibit increased number of arm entries in the Y maze

A. Number of arm entries in the Y maze spontaneous alternation task (SAT) over a 10 minute experimental period. **p=0.0086, *p=0.0312 by 2-Way between-subjects ANOVA with Tukey's post-hoc comparisons (n=16-20/group). P301S Tia1+/+ and P301S Tia1+/- mice were not significantly different. Error bars denote means ± SEM.

Supplementary Figure 6 PS19 mice exhibit hyperactive locomotor activity and reduced anxiety behaviors independent of Tial genotype

A-D. P301S transgene expression increased distance traveled (A), mean speed (B), and center time (C) in the OF task, while decreasing freezing time (D). Main effect of P301S Tau transgene by 2-way between-subjects ANOVA (p=ns) for total distance traveled, mean speed, center time, and freezing time. Error bars denote means ± SEM.

Supplementary Figure 7 TIA1 reduction elicits a biphasic change in tau phosphorylation in PS19 mice

A. IHC of DAPI (blue), NeuN (green), and CP13 phospho (S202)-tau (red) in 3 (top panels) and 6 (bottom) month CA3 in non-transgenic (WT Tau) and PS19 (P301S Tau) mice. B-C. Quantification of CP13 (from A) and AT8 (S202/T205) phospho-tau immunofluorescence at 3 months in CA1 and CA3. *p<0.05 **p<0.01 by unpaired Student's t-test (n=3-5/group). D. Quantification of CP13 immunofluorescence at 6 months in CA3 from A. **p=0.0044 by unpaired Student's t-test (n=4-5/group). Error bars represent means ± SEM.

Supplementary Figure 8 TIA1 reduction increases levels of phosphorylated tau in aged PS19 mice

A. Immunoblot analysis of PHF1 (S396/S404) phospho-tau, CP13, Tau13 (total tau), and a-tubulin levels in total (RIPA-soluble) brain lysates of 6-month P301S Tia1+/+ and P301S Tia1+/- mice. Each lane corresponds to a different mouse from the cohort. B-C. Quantification of PHF1+ (B), CP13+ (C), and total (D) tau in A. PHF1 and CP13 phospho-tau levels were normalized to total tau levels (Tau13) detected in each sample. #p= 0.0981 *p=0.0276 **p=0.0079 by unpaired Student's t-test (n=3/group). Error bars denote means ± SEM.

Supplementary Figure 9 The number of Gallyas Silver neurofibrillary tangles does not correlate with neuronal loss in 9 month PS19 mice

Number of Gallyas Silver+ tangles plotted against the number of Nissl+ neurons in CA3 of the same animals for 9 month P301S Tia1+/+ and P301S Tia1+/- mice (r2= 0.07).

Supplementary Figure 10 TIA1 reduction decreases soluble tau oligomers in PS19 mice

A-C. Quantification of conformational (TNT1, TOC1) and total tau species in the soluble (S1) fraction of 9 month P301S Tia1+/+ and P301S Tia1+/- cortex, as detected by non-denaturing ELISA using TNT1 (A), TOC1 (B), and Tau5 (C) antibodies. The TNT1 and TOC1 levels plotted in A and B were normalized to the level of Tau5 (total tau) detected in the same sample. Concentrations in each sample were determined by comparison to a standard curve generated from recombinant tau. #p=0.1420 **p= 0.0073 by unpaired Student's t-tests (n=3/group). Error bars denote means ± SEM.

Supplementary Figure 11 RNA binding proteins are enriched in the S1p tau oligomer fraction of PS19 cortex

A. Gene ontology (GO) analysis of proteins identified by OrbiTrap liquid chromatography tandem mass spectrometry (LC-MS/MS) are enriched (FDR < 0.05) for annotation terms related to mRNA binding and RNA metabolism. B. Immunoblot of the RNA binding proteins (RBPs) PABP and DDX6 in the S1p and P3 fractions of P301S Tia1+/+ and P301S Tia1+/- cortex, validating the change identified by LC-MS/MS. Each lane corresponds to a different mouse from the cohort.

Supplementary Figure 12 TIA disrupts fibrillization of pTau

Fibrillization of GSK3|3 phosphorylated recombinant Tau was induced using dextran sulfate (DS) and RNA (pTau+Ctrl). In the presence of recombinant TIA1, pTau fibril length was significantly reduced. BSA was used as a negative control for presence of additional protein in the Tau fibrillization assay. Scatter plot of individual Tau fibril lengths (nm) measured by EM with bar at mean, box representing quartiles and whiskers representing SEM. ANOVA posthoc. *** p<0.001. Numbers assigned to data points in order in which they are measured.

Supplementary Figure 13 TIA1 selectively associates with pre-fibrillar tau aggregates

A. Representative EM image of pTau + TIA1 assembly reaction double immuno-gold labeled with antibodies to TOC1 and TIA1. While TIA1 (15 nm particles) exhibited no labeling of tau fibrils (i), TOC1 (6 nm particles) aggregates (ii) almost always exhibited co-labeling of TIA1. Scale bar = 500 nm.

Supplementary Figure 14 Controls for TOC1 immunohistochemical labeling

TOC1 antibody (green) did not label neurons in frontal cortex in A) WT mice, but did label neurons in B) P301S tau mice (9 months). DAPI = blue. Scale bar = 5 ^m.

Supplementary Figure 15 Model for regulation of tau oligomerization by TIA1

We propose that TIA1 binds and stabilizes oligomeric tau, which is a very toxic form. Reducing TIA1 removes the stabilization and allows greater production of tau fibrils. TIA1 reduction also inhibits the hyperactive stress granule response, which allows TIA1 and other RBPs to re-localize to their normal physiological functions, such as RNA splicing. The reduction in oligomeric tau and rescue of RBP functions associated with reducing TIA1 leads to neuroprotection and increased survival.

Supplementary Figure 16 Full immunoblot image of Figure 1A top panel probing for TIA1

Samples from total brain lysates of 3 month old P301S Tia1+/+ and P301S Tia1+/- mice.

Supplementary Figure 17 Full immunoblot image of Figure 1A bottom panel probing for Actin

Samples from total brain lysates of 3 month old P301S Tia1+/+ and P301S Tia1+/- mice.

Supplementary Figure 18 Full immunoblot image of Figure 2C top panel probing for Tau (Tau13)

Samples from microtubule-bound pellet and unbound supernatant in 6 and 9 month old WT, Tia+/-, P301S Tia1+/+ and P301S Tia1+/- mouse total cortex.

Supplementary Figure 19 Full immunoblot image of Figure 2C bottom panel probing for tubulin

Samples from microtubule-bound pellet and unbound supernatant in 6 and 9 month old WT, Tia+/-, P301S Tia1+/+ and P301S Tia1+/- mouse total cortex.

Supplementary Figure 20 Full immunoblot image of short exposure panels in Figure 6A probing for Tau (Tau13)

Image from short exposure (3mins) of total tau immunoblots of samples from S1p (left) and P3 (right) fractions of 6 and 9 month old P301S Tia1+/+ and P301S Tia1+/- mice.

Supplementary Figure 21 Full immunoblot image of long exposure panels in Figure 6A probing for Tau (Tau13)

Image from long exposure (30mins) of total tau immunoblots of samples from S1p (left) and P3 (right) fractions of 6 and 9 month old P301S Tia1+/+ and P301S Tia1+/- mice.

Supplementary information

Supplementary Figures 1–21

Life Sciences Reporting Summary

Supplementary Table 1

Lifespan data for P301S Tia1+/+ and P301S Tia1+/- mice

Supplementary Table 2

Proteomic components of the S1p fractions of PS19 cortices detected by LC-MS-MS

Supplementary Table 3

Table of absolute p values from statistical tests

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Apicco, D.J., Ash, P.E.A., Maziuk, B. et al. Reducing the RNA binding protein TIA1 protects against tau-mediated neurodegeneration in vivo. Nat Neurosci 21, 72–80 (2018). https://doi.org/10.1038/s41593-017-0022-z

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