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Truncated tau interferes with the autophagy and endolysosomal pathway and results in lipid accumulation

Pollack, Saskia J., Dakkak, Dina, Guo, Tong, Chennell, George, Gomez-Suaga, Patricia, Noble, Wendy, Jimenez-Sanchez, Maria, Hanger, Diane P.·2024·Cellular and Molecular Life Sciences
DOI 10.1007/s00018-024-05337-6PMC PMC11335226

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Abstract

The autophagy-lysosomal pathway plays a critical role in the clearance of tau protein aggregates that deposit in the brain in tauopathies, and defects in this system are associated with disease pathogenesis. Here, we report that expression of Tau35, a tauopathy-associated carboxy-terminal fragment of tau, leads to lipid accumulation in cell lines and primary cortical neurons. Our findings suggest that this is likely due to a deleterious block of autophagic clearance and lysosomal degradative capacity by Tau35. Notably, upon induction of autophagy by Torin 1, Tau35 inhibited nuclear translocation of transcription factor EB (TFEB), a key regulator of lysosomal biogenesis. Both cell lines and primary cortical neurons expressing Tau35 also exhibited changes in endosomal protein expression. These findings implicate autophagic and endolysosomal dysfunction as key pathological mechanisms through which disease-associated tau fragments could lead to the development and progression of tauopathy.

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Figures

Fig. 1 Tau35 expression leads to an increase in neutral lipid droplets. a CHO cells labelled with BODIPY 493/503 to label neutral lipid droplets. Scale bar = 10 µm. (ai) Number of BODIPY puncta per cell/cell body area. N = 3 independent experiments (30 cells). One-way ANOVA with Tukey’s multiple comparisons test, ***P < 0.005. b Primary cortical neurons labelled with BODIPY 493/503 to label neutral lipid droplets. Scale bar = 10 µm. (bi) Number of BODIPY puncta per soma area. N = 3 neuron preparations (38–48 cell bodies). Unpaired t-test, ****P < 0.001
Fig. 1 Tau35 expression leads to an increase in neutral lipid droplets. a CHO cells labelled with BODIPY 493/503 to label neutral lipid droplets. Scale bar = 10 µm. (ai) Number of BODIPY puncta per cell/cell body area. N = 3 independent experiments (30 cells). One-way ANOVA with Tukey’s multiple comparisons test, ***P < 0.005. b Primary cortical neurons labelled with BODIPY 493/503 to label neutral lipid droplets. Scale bar = 10 µm. (bi) Number of BODIPY puncta per soma area. N = 3 neuron preparations (38–48 cell bodies). Unpaired t-test, ****P < 0.001CC BY · PubMed Central
Fig. 2 Tau35 expression leads to a decrease in LC3-labelled autophagosomes and autolysosomes. a CHO cells transfected with EGFP-LC3 plasmid (green). Scale bar = 10 µm. (ai) Graph shows the number of EGFP-LC3 puncta per cell area. N = 3 independent experiments (70–100 cells). Kruskal–Wallis test with Dunn’s multiple comparisons test, ****P < 0.0001, **P < 0.005. b Immunofluorescence labelling of CHO cells with an LC3 antibody. Scale bar = 10 µm. (bi) Graph shows the number of LC3 puncta per cell area. N = 3 independent experiments. One-way ANOVA with Tukey’s multiple comparisons test, ****P < 0.0001, **P < 0.005. c CHO cells transduced with mCherry-GFP-LC3 lentivirus. Scale bar = 10 µm. Graphs show the number of (ci) mCherry + GFP + (autophagosomes) and (cii) mCherry + GFP− puncta (autolysosomes) per cell area. N = 3 independent experiments. Kruskal–Wallis test with Dunn’s multiple comparisons test, ****P < 0.0001. d Primary cortical neurons from WT and Tau35 mice, transduced with mCherry-GFP-LC3 lentivirus. Blue arrowheads point to autolysosomes. White arrowheads point to autophagosomes. Scale bar = 10 µm. Graphs show the number of (di) mCherry + GFP + (autophagosomes) and (dii) mCherry + GFP− puncta (autolysosomes) per soma area. N = 3 independent experiments. Unpaired t- test, *P < 0.05
Fig. 2 Tau35 expression leads to a decrease in LC3-labelled autophagosomes and autolysosomes. a CHO cells transfected with EGFP-LC3 plasmid (green). Scale bar = 10 µm. (ai) Graph shows the number of EGFP-LC3 puncta per cell area. N = 3 independent experiments (70–100 cells). Kruskal–Wallis test with Dunn’s multiple comparisons test, ****P < 0.0001, **P < 0.005. b Immunofluorescence labelling of CHO cells with an LC3 antibody. Scale bar = 10 µm. (bi) Graph shows the number of LC3 puncta per cell area. N = 3 independent experiments. One-way ANOVA with Tukey’s multiple comparisons test, ****P < 0.0001, **P < 0.005. c CHO cells transduced with mCherry-GFP-LC3 lentivirus. Scale bar = 10 µm. Graphs show the number of (ci) mCherry + GFP + (autophagosomes) and (cii) mCherry + GFP− puncta (autolysosomes) per cell area. N = 3 independent experiments. Kruskal–Wallis test with Dunn’s multiple comparisons test, ****P < 0.0001. d Primary cortical neurons from WT and Tau35 mice, transduced with mCherry-GFP-LC3 lentivirus. Blue arrowheads point to autolysosomes. White arrowheads point to autophagosomes. Scale bar = 10 µm. Graphs show the number of (di) mCherry + GFP + (autophagosomes) and (dii) mCherry + GFP− puncta (autolysosomes) per soma area. N = 3 independent experiments. Unpaired t- test, *P < 0.05CC BY · PubMed Central
Fig. 3 Tau35 expression leads to reduced lysosomal protein expression and reduced acidic organelles. a Immunofluorescence labelling of CHO cells with antibodies to LAMP2 (green) and cathepsin D (red). Scale bar = 10 µm. The number of (ai) LAMP2 and (aii) cathepsin D puncta per cell area. N = 3 independent experiments (30 cells). Welch ANOVA with Dunnett’s T3 multiple comparisons test, ****P < 0.0001. b CHO cells labelled with LysoTracker Red. Scale bar = 10 µm. Graphs show the (bi) number of LysoTracker puncta per cell and (bii) puncta area per cell. N = 3 independent experiments (32–37 cells). One-way ANOVA with Tukey’s multiple comparisons test, *P < 0.05, **P < 0.005, ****P < 0.0001. c, d Immunofluorescence labelling of primary cortical neurons (DIV 14) from WT and Tau35 mice with antibodies to LAMP2 (green), cathepsin D (green) and MAP2 (magenta). Scale bar = 10 µm. Graphs show quantification of (ci) LAMP2 fluorescence intensity per soma area and (cii) LAMP2 puncta size (N = 3 neuron preparations, 57–79 cell bodies) and fluorescence intensity per soma area for (di) cathepsin D (Cat D) (N = 3 neuron preparations, 30–35 cell bodies). Unpaired t-test ****P < 0.0001. e Primary cortical neurons from WT and Tau35 mice labelled with LysoTracker Red and imaged live for 2 min. Images show the first time-frame. Scale bar = 10 µm. Graphs show the (ei) the area of LysoTracker puncta, (eii) the number of LysoTracker puncta per soma area, and (eiii) the mean track speed of LysoTracker puncta over 2 min. (N = 3 neuronal preparations, 20–30 fields of view/cell bodies). Unpaired t-test **P < 0.01, ***P < 0.001
Fig. 3 Tau35 expression leads to reduced lysosomal protein expression and reduced acidic organelles. a Immunofluorescence labelling of CHO cells with antibodies to LAMP2 (green) and cathepsin D (red). Scale bar = 10 µm. The number of (ai) LAMP2 and (aii) cathepsin D puncta per cell area. N = 3 independent experiments (30 cells). Welch ANOVA with Dunnett’s T3 multiple comparisons test, ****P < 0.0001. b CHO cells labelled with LysoTracker Red. Scale bar = 10 µm. Graphs show the (bi) number of LysoTracker puncta per cell and (bii) puncta area per cell. N = 3 independent experiments (32–37 cells). One-way ANOVA with Tukey’s multiple comparisons test, *P < 0.05, **P < 0.005, ****P < 0.0001. c, d Immunofluorescence labelling of primary cortical neurons (DIV 14) from WT and Tau35 mice with antibodies to LAMP2 (green), cathepsin D (green) and MAP2 (magenta). Scale bar = 10 µm. Graphs show quantification of (ci) LAMP2 fluorescence intensity per soma area and (cii) LAMP2 puncta size (N = 3 neuron preparations, 57–79 cell bodies) and fluorescence intensity per soma area for (di) cathepsin D (Cat D) (N = 3 neuron preparations, 30–35 cell bodies). Unpaired t-test ****P < 0.0001. e Primary cortical neurons from WT and Tau35 mice labelled with LysoTracker Red and imaged live for 2 min. Images show the first time-frame. Scale bar = 10 µm. Graphs show the (ei) the area of LysoTracker puncta, (eii) the number of LysoTracker puncta per soma area, and (eiii) the mean track speed of LysoTracker puncta over 2 min. (N = 3 neuronal preparations, 20–30 fields of view/cell bodies). Unpaired t-test **P < 0.01, ***P < 0.001CC BY · PubMed Central
Fig. 4 Tau35 expression disrupts the nuclear translocation of TFEB. a CHO cells transfected with a TFEB-GFP plasmid (green). Nuclei are labelled with Hoechst 33342 (blue). Scale bar = 10 µm. Note that high exposure images are shown to enable observation of the cytoplasmic TFEB-GFP signal. (ai) The percentage (%) of cells with nuclear TFEB-GFP (N = 3 independent experiments, 22–25 fields of view). One-way ANOVA with Tukey’s multiple comparisons test, **P < 0.01. b Western blots of CHO nuclear-cytoplasmic fractionation lysates, probed with antibodies to TFEB, GAPDH and Histone H3. (bi) TFEB levels in cytoplasm and nucleus were normalised to GAPDH or Histone H3 respectively and the normalised nuclear/cytoplasmic TFEB ratio is shown after vehicle (DMSO) or 1 µM Torin 1 treatment (1 h) (N = 3 independent experiments). Two-way ANOVA with Sidak’s multiple comparisons test, *P < 0.05, ****P < 0.0001. c Primary cortical neurons (DIV 5) transfected with TFEB-GFP (green) and mCherry (red, to define neuronal morphology and to distinguish the cytoplasmic region) and treated with vehicle (DMSO) or 250 nM Torin 1 (6 h). Scale bar = 10 µm. (ci) the intensity of TFEB-GFP per nucleus area and (cii) percentage (%) of cells with nuclear TFEB-GFP, using the WT vehicle average intensity as a threshold (N = 3 neuron preparations, 32–33 cells). Two-way ANOVA with Sidak’s multiple comparisons test, *P < 0.05, **P < 0.01, ****P < 0.0001
Fig. 4 Tau35 expression disrupts the nuclear translocation of TFEB. a CHO cells transfected with a TFEB-GFP plasmid (green). Nuclei are labelled with Hoechst 33342 (blue). Scale bar = 10 µm. Note that high exposure images are shown to enable observation of the cytoplasmic TFEB-GFP signal. (ai) The percentage (%) of cells with nuclear TFEB-GFP (N = 3 independent experiments, 22–25 fields of view). One-way ANOVA with Tukey’s multiple comparisons test, **P < 0.01. b Western blots of CHO nuclear-cytoplasmic fractionation lysates, probed with antibodies to TFEB, GAPDH and Histone H3. (bi) TFEB levels in cytoplasm and nucleus were normalised to GAPDH or Histone H3 respectively and the normalised nuclear/cytoplasmic TFEB ratio is shown after vehicle (DMSO) or 1 µM Torin 1 treatment (1 h) (N = 3 independent experiments). Two-way ANOVA with Sidak’s multiple comparisons test, *P < 0.05, ****P < 0.0001. c Primary cortical neurons (DIV 5) transfected with TFEB-GFP (green) and mCherry (red, to define neuronal morphology and to distinguish the cytoplasmic region) and treated with vehicle (DMSO) or 250 nM Torin 1 (6 h). Scale bar = 10 µm. (ci) the intensity of TFEB-GFP per nucleus area and (cii) percentage (%) of cells with nuclear TFEB-GFP, using the WT vehicle average intensity as a threshold (N = 3 neuron preparations, 32–33 cells). Two-way ANOVA with Sidak’s multiple comparisons test, *P < 0.05, **P < 0.01, ****P < 0.0001CC BY · PubMed Central
Fig. 5 Tau35 expression disrupts the expression of early and late endosomal proteins. a Immunofluorescence of CHO cells labelled with EEA1 antibody (red). Nuclei are shown with DAPI (blue). Scale bar = 10 μm. (ai) Graph shows EEA1 puncta size (N = 3 independent experiments, 30–45 cells). One-way ANOVA with Tukey’s multiple comparisons test, ***P < 0.001. b Immunofluorescence of CHO cells labelled with Rab7 antibody (green) and Hoechst 33342 (blue). Scale bar = 10 μm. (bi) Graph shows intensity per cell area (N = 3 independent experiments, 30–45 cells). One-way ANOVA with Tukey’s multiple comparisons test, **P < 0.005 ***P < 0.001. c Immunofluorescence of primary cortical neurons labelled with EEA1 (green) and MAP2 (magenta) antibodies. Scale bar = 10 μm. (ci) Graph shows puncta size (N = 3 independent neuron preparations, 35 cell bodies). Unpaired t-test, **P < 0.01. d Immunofluorescence of primary cortical neurons labelled with Rab7 (green) and MAP2 (magenta) antibodies. Scale bar = 10 μm. (di) Graph shows intensity per soma (N = 3 independent neuron preparations, 43–47 cell bodies). Unpaired t-test, **P < 0.01
Fig. 5 Tau35 expression disrupts the expression of early and late endosomal proteins. a Immunofluorescence of CHO cells labelled with EEA1 antibody (red). Nuclei are shown with DAPI (blue). Scale bar = 10 μm. (ai) Graph shows EEA1 puncta size (N = 3 independent experiments, 30–45 cells). One-way ANOVA with Tukey’s multiple comparisons test, ***P < 0.001. b Immunofluorescence of CHO cells labelled with Rab7 antibody (green) and Hoechst 33342 (blue). Scale bar = 10 μm. (bi) Graph shows intensity per cell area (N = 3 independent experiments, 30–45 cells). One-way ANOVA with Tukey’s multiple comparisons test, **P < 0.005 ***P < 0.001. c Immunofluorescence of primary cortical neurons labelled with EEA1 (green) and MAP2 (magenta) antibodies. Scale bar = 10 μm. (ci) Graph shows puncta size (N = 3 independent neuron preparations, 35 cell bodies). Unpaired t-test, **P < 0.01. d Immunofluorescence of primary cortical neurons labelled with Rab7 (green) and MAP2 (magenta) antibodies. Scale bar = 10 μm. (di) Graph shows intensity per soma (N = 3 independent neuron preparations, 43–47 cell bodies). Unpaired t-test, **P < 0.01CC BY · PubMed Central

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Metadata

Authors
Pollack, S. J., Dakkak, D., Guo, T., Chennell, G., Gomez-Suaga, P., Noble, W., Jimenez-Sanchez, M., & Hanger, D. P.
ORCID
Jimenez-Sanchez, Maria
Venue
Cellular and Molecular Life Sciences
Publisher
Springer Science and Business Media LLC
Published
2024-07-15
Volume
81
Issue
1
ISSN
  • 1420-682X
  • 1420-9071
DOI
10.1007/s00018-024-05337-6
PMC
PMC11335226
Cited by
14
References
12
Language
en
Licence
Funders
  • Alzheimer's Society (AS-PG-18b-012)
  • Alzheimer Society (AS-PG-18b-012)
  • Motor Neurone Disease Association (Gomez-Suaga/Oct17/967/799)
  • Instituto de Salud Carlos III (IHMC22/00025)
  • Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CB06/05/0041)
  • Medical Research Council (MR/V036947/1)

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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