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RNA induces unique tau strains and stabilizes Alzheimer’s disease seeds

Zwierzchowski-Zarate, Amy N., Mendoza-Oliva, Aydé, Kashmer, Omar M., Collazo-Lopez, Josue E., White, Charles L., Diamond, Marc I.·2022·Journal of Biological Chemistry
DOI 10.1016/j.jbc.2022.102132PMC PMC9364032

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Figure 1 Tau nonselectively binds RNA yet seeding and fibrilization are specific.A, BLI with tau immobilized onto AR2G biosensors and exposed to increasing concentrations of PolyA, or C RNA (half-log dilutions: 0.13 μM (red), 0.4 μM (dark blue), 1.3 μM (green), 4 μM (light blue), 13 μM (orange), and 41 μM (black)). Tau bound all RNA with similar avidity, association, and dissociation rates. Figure shows representative data of polyA or polyC RNA binding to BLI AR2G sensors loaded with tau. KDAPP calculated as mean of three independent experiments. Binding (nm) refers to the wavelength perturbation in reflected light from the biosensor. Red lines represent curves fit to primary data. See Table 1 and Fig. S1 for more data on these experiments. B, tau monomer incubated 24 h with nucleic acid before transduction of v2L biosensors. Intracellular aggregation was quantified as % FRET positive via flow cytometry. Specific nucleic acids induced seed-competency in tau (human total RNA p < 0.0001, polyA RNA p < 0.0001, ssDNA Seq1 p = 0.0007, ssDNA Seq1′ p = 0.0002) while others did not (polyU RNA p = 0.98, polyC RNA p = 0.99, dsRNA p = 0.99, dsDNA p = 0.99, RNA/DNA p = 0.98). p values calculated with one-way ANOVA, post-hoc Dunnett’s multiple comparisons test. C, after 1 week with indicated inducer, tau was deposited on 400CF grids (4 μM) and stained with 2% uranyl acetate. Grids were scanned with TEM for fibrils, and representative images are shown. No fibrils were seen for no inducer, polyU, or polyC. Fibrils were observed only in conditions that induced seeding (polyA). Scale bar = 500 nm. D, tau monomer incubated with various molar ratios of polyA for 24 h before induction of biosensors. 2:1 Tau to RNA (8 μM:4 μM) ratio produced optimal seeding. E and F, seeding of tau following incubation with various lengths (nt) of polyA RNA for 2 (E) or 7 (F) days before transducing biosensors. >40 nt was required for tau seeding. (2 days versus 0, p = 0.97 10mer, p > 0.99 20mer, p = 0.99 30mer, p < 0.0001 40mer; 7 days versus 0, p = 0.99 10mer, p > 0.99 20mer, p = 0.15 30mer, p < 0.0001 40mer) p values calculated with one-way ANOVA, post-hoc Dunnett’s multiple comparisons test. All seeding data represents two experimental replicates, each performed in technical triplicate. These experiments are representative of similar studies performed 19 times overall for (B), and five times overall for (D-F). Error bars = S.D. ∗∗∗∗p < 0.0001, ∗∗∗p < 0.001.
Figure 1 Tau nonselectively binds RNA yet seeding and fibrilization are specific.A, BLI with tau immobilized onto AR2G biosensors and exposed to increasing concentrations of PolyA, or C RNA (half-log dilutions: 0.13 μM (red), 0.4 μM (dark blue), 1.3 μM (green), 4 μM (light blue), 13 μM (orange), and 41 μM (black)). Tau bound all RNA with similar avidity, association, and dissociation rates. Figure shows representative data of polyA or polyC RNA binding to BLI AR2G sensors loaded with tau. KDAPP calculated as mean of three independent experiments. Binding (nm) refers to the wavelength perturbation in reflected light from the biosensor. Red lines represent curves fit to primary data. See Table 1 and Fig. S1 for more data on these experiments. B, tau monomer incubated 24 h with nucleic acid before transduction of v2L biosensors. Intracellular aggregation was quantified as % FRET positive via flow cytometry. Specific nucleic acids induced seed-competency in tau (human total RNA p < 0.0001, polyA RNA p < 0.0001, ssDNA Seq1 p = 0.0007, ssDNA Seq1′ p = 0.0002) while others did not (polyU RNA p = 0.98, polyC RNA p = 0.99, dsRNA p = 0.99, dsDNA p = 0.99, RNA/DNA p = 0.98). p values calculated with one-way ANOVA, post-hoc Dunnett’s multiple comparisons test. C, after 1 week with indicated inducer, tau was deposited on 400CF grids (4 μM) and stained with 2% uranyl acetate. Grids were scanned with TEM for fibrils, and representative images are shown. No fibrils were seen for no inducer, polyU, or polyC. Fibrils were observed only in conditions that induced seeding (polyA). Scale bar = 500 nm. D, tau monomer incubated with various molar ratios of polyA for 24 h before induction of biosensors. 2:1 Tau to RNA (8 μM:4 μM) ratio produced optimal seeding. E and F, seeding of tau following incubation with various lengths (nt) of polyA RNA for 2 (E) or 7 (F) days before transducing biosensors. >40 nt was required for tau seeding. (2 days versus 0, p = 0.97 10mer, p > 0.99 20mer, p = 0.99 30mer, p < 0.0001 40mer; 7 days versus 0, p = 0.99 10mer, p > 0.99 20mer, p = 0.15 30mer, p < 0.0001 40mer) p values calculated with one-way ANOVA, post-hoc Dunnett’s multiple comparisons test. All seeding data represents two experimental replicates, each performed in technical triplicate. These experiments are representative of similar studies performed 19 times overall for (B), and five times overall for (D-F). Error bars = S.D. ∗∗∗∗p < 0.0001, ∗∗∗p < 0.001.CC BY · PubMed Central
Figure 2 Stabilization of tau fibrils and seeds in vitro.A, tau fibrils preformed with polyA RNA or heparin were treated with RNase (T1 and A, 316 U/μl and 3.2 mg/ml), DNase (I, 633 U/μl), or heparinase I (3797 U/ml) for 24 h before transduction of biosensors. (+) signifies RNase treatment added to fibrils at same time as seeding, with no pre-incubation. Seeds formed with polyA were sensitive to RNase treatment (p < 0.0001). RNase added directly to seeds at the time of seeding had no effect (p = 0.49). DNase and heparinase treatment did not affect seeds formed by polyA (p = 0.99 and 0.97). Seeds formed with heparin were sensitive to heparinase treatment (p < 0.0001), but not RNase or DNase (p = 0.09 RNase, p > 0.99 immediate RNase, p = 0.24 DNase). p values were calculated with one-way repeated measures ANOVA, post-hoc Dunnett’s multiple comparisons test, comparing control to enzyme treated conditions for both polyA and heparin fibrils. Seeding data represents two experimental replicates, each performed in technical triplicate. These experiments are representative of similar studies performed 15 times overall. Error bars = S.D. B, TEM 400CF grids containing tau (4 μM) stained with 2% UA. All grids were scanned; representative images are shown. Scale bar = 200 nm. Fibrils formed by polyA lose integrity after exposure to RNase, but not heparinase. Heparin fibrils were undetectable after heparinase treatment, but not RNase. FRET, fluorescence resonance energy transfer. ∗∗∗∗p < 0.0001.
Figure 2 Stabilization of tau fibrils and seeds in vitro.A, tau fibrils preformed with polyA RNA or heparin were treated with RNase (T1 and A, 316 U/μl and 3.2 mg/ml), DNase (I, 633 U/μl), or heparinase I (3797 U/ml) for 24 h before transduction of biosensors. (+) signifies RNase treatment added to fibrils at same time as seeding, with no pre-incubation. Seeds formed with polyA were sensitive to RNase treatment (p < 0.0001). RNase added directly to seeds at the time of seeding had no effect (p = 0.49). DNase and heparinase treatment did not affect seeds formed by polyA (p = 0.99 and 0.97). Seeds formed with heparin were sensitive to heparinase treatment (p < 0.0001), but not RNase or DNase (p = 0.09 RNase, p > 0.99 immediate RNase, p = 0.24 DNase). p values were calculated with one-way repeated measures ANOVA, post-hoc Dunnett’s multiple comparisons test, comparing control to enzyme treated conditions for both polyA and heparin fibrils. Seeding data represents two experimental replicates, each performed in technical triplicate. These experiments are representative of similar studies performed 15 times overall. Error bars = S.D. B, TEM 400CF grids containing tau (4 μM) stained with 2% UA. All grids were scanned; representative images are shown. Scale bar = 200 nm. Fibrils formed by polyA lose integrity after exposure to RNase, but not heparinase. Heparin fibrils were undetectable after heparinase treatment, but not RNase. FRET, fluorescence resonance energy transfer. ∗∗∗∗p < 0.0001.CC BY · PubMed Central
Figure 3 RNA inducer dictates aggregate maintenance and strain identity.A, Tau seeds derived from different nucleic acid sources were transduced into DS1 cells, and single cells were sorted into 96-well plates and monitored over time. Certain nucleic acids (human, polyA) created more stable strains than others (ssDNA, yeast), which lost aggregates or sectored almost completely. N = 130 derived from human RNA, 228 from polyA, 220 from DNA, and 98 from yeast RNA. B, stable colonies containing inclusions were imaged using an In Cell Analyzer 6000, and resulting images were scored for morphology, blinded to the method of seed induction. Distribution of morphologies varied by inducer. N = 78 derived from human RNA, 99 from polyA, and 7 from ssDNA, 1 from yeast. C, exemplars of morphologies. Scale bar = 6 μm.
Figure 3 RNA inducer dictates aggregate maintenance and strain identity.A, Tau seeds derived from different nucleic acid sources were transduced into DS1 cells, and single cells were sorted into 96-well plates and monitored over time. Certain nucleic acids (human, polyA) created more stable strains than others (ssDNA, yeast), which lost aggregates or sectored almost completely. N = 130 derived from human RNA, 228 from polyA, 220 from DNA, and 98 from yeast RNA. B, stable colonies containing inclusions were imaged using an In Cell Analyzer 6000, and resulting images were scored for morphology, blinded to the method of seed induction. Distribution of morphologies varied by inducer. N = 78 derived from human RNA, 99 from polyA, and 7 from ssDNA, 1 from yeast. C, exemplars of morphologies. Scale bar = 6 μm.CC BY · PubMed Central
Figure 4 RNA stabilizes soluble seeds from AD brain. Homogenate from AD brain was fractionated in sarkosyl via ultracentrifugation. The supernatant (sup) was further fractionated using SEC. A, resultant fractions were treated with RNase, DNase, or vehicle for 24 h and seeded onto v2L biosensors. The percentage of FRET-positive cells was determined at 48 h. Soluble AD seeds (Sup, >10mer, ∼10mer, trimer, monomer) were highly sensitive to RNase (Sup, >10mer, ∼10mer p < 0.0001, trimer p = 0.0025, monomer p = 0.015, multiple unpaired t tests as compared to control) but not DNase (Sup p = 0.54, >10mer p = 0.68, ∼10mer p = 0.74, trimer p = 0.49, monomer p = 0.45, multiple unpaired t tests as compared to control). Sarkosyl insoluble (SI) AD fibrils were unchanged in all conditions (p = 0.65 RNase versus control, p = 0.28 DNase versus control). Graphs represent data from two experimental replicates, each performed in technical triplicate. These experiments are representative of similar studies performed 12 times overall. Error bars = S.D. B, data from A normalized to untreated control seeding (% FRET positive). AD, Alzheimer’s disease; FRET, fluorescence resonance energy transfer; SEC, size-exclusion chromatography. ∗∗∗∗p < 0.0001, ∗∗∗p < 0.001, ∗∗p < 0.01, ∗p < 0.05.
Figure 4 RNA stabilizes soluble seeds from AD brain. Homogenate from AD brain was fractionated in sarkosyl via ultracentrifugation. The supernatant (sup) was further fractionated using SEC. A, resultant fractions were treated with RNase, DNase, or vehicle for 24 h and seeded onto v2L biosensors. The percentage of FRET-positive cells was determined at 48 h. Soluble AD seeds (Sup, >10mer, ∼10mer, trimer, monomer) were highly sensitive to RNase (Sup, >10mer, ∼10mer p < 0.0001, trimer p = 0.0025, monomer p = 0.015, multiple unpaired t tests as compared to control) but not DNase (Sup p = 0.54, >10mer p = 0.68, ∼10mer p = 0.74, trimer p = 0.49, monomer p = 0.45, multiple unpaired t tests as compared to control). Sarkosyl insoluble (SI) AD fibrils were unchanged in all conditions (p = 0.65 RNase versus control, p = 0.28 DNase versus control). Graphs represent data from two experimental replicates, each performed in technical triplicate. These experiments are representative of similar studies performed 12 times overall. Error bars = S.D. B, data from A normalized to untreated control seeding (% FRET positive). AD, Alzheimer’s disease; FRET, fluorescence resonance energy transfer; SEC, size-exclusion chromatography. ∗∗∗∗p < 0.0001, ∗∗∗p < 0.001, ∗∗p < 0.01, ∗p < 0.05.CC BY · PubMed Central
Figure 5 Model of RNA:tau seeding and strain propagation.A, RNA serves as a sequence-specific inducer of tau seeds and strains. Stable cellular replication of a given strain depends on compatible RNA to be present as a co-factor. B, in the absence of compatible RNA, a given RNA-induced strain will replicate inefficiently.
Figure 5 Model of RNA:tau seeding and strain propagation.A, RNA serves as a sequence-specific inducer of tau seeds and strains. Stable cellular replication of a given strain depends on compatible RNA to be present as a co-factor. B, in the absence of compatible RNA, a given RNA-induced strain will replicate inefficiently.CC BY · PubMed Central

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Cited by

Metadata

Authors
Zwierzchowski-Zarate, A. N., Mendoza-Oliva, A., Kashmer, O. M., Collazo-Lopez, J. E., White, C. L., & Diamond, M. I.
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2022-08
Volume
298
Issue
8
Pages
102132
ISSN
0021-9258
DOI
10.1016/j.jbc.2022.102132
PMC
PMC9364032
Cited by
45
References
21
Language
en
Licence
Funders
  • Chan Zuckerberg Initiative
  • National Institutes of Health
  • National Institute on Aging (1R01AG059689)

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