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Tau Protein as a New Regulator of Cellular Prion Protein Transcription

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Abstract

Cellular prion protein (PrPC) is largely responsible for transmissible spongiform encephalopathies (TSEs) when it becomes the abnormally processed and protease resistant form PrPSC. Physiological functions of PrPC include protective roles against oxidative stress and excitotoxicity. Relevantly, PrPC downregulates tau levels, whose accumulation and modification are a hallmark in the advance of Alzheimer’s disease (AD). In addition to the accumulation of misfolded proteins, in the initial stages of AD-affected brains display both increased reactive oxygen species (ROS) markers and levels of PrPC. However, the factors responsible for the upregulation of PrPC are unknown. Thus, the aim of this study was to uncover the different molecular actors promoting PrPC overexpression. In order to mimic early stages of AD, we used β-amyloid-derived diffusible ligands (ADDLs) and tau cellular treatments, as well as ROS generation, to elucidate their particular roles in human PRNP promoter activity. In addition, we used specific chemical inhibitors and site-specific mutations of the PRNP promoter sequence to analyze the contribution of the main transcription factors involved in PRNP transcription under the analyzed conditions. Our results revealed that tau is a new modulator of PrPC expression independently of ADDL treatment and ROS levels. Lastly, we discovered that the JNK/c-jun-AP-1 pathway is involved in increased PRNP transcription activity by tau but not in the promoter response to ROS.

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Acknowledgments

We wish to thank Prof. John Collinge (head of the Medical Research Council Prion Unit at University College London, UCL, UK) for providing plasmid pPrPS2.7, Tom Yohannan for editorial advice, and Miriam Segura-Feliu for technical support. We also thank the Core facilities of IBEC for technical help.

Funding

This research was supported by the projects PRPSEM with reference (RTI2018-099773-B-I00) and PRIONET (AGL2017-90665-REDT), the Generalitat de Catalunya (SGR2017-648), CIBERNED (CNED-2018-2), and CERCA Programme/Generalitat de Catalunya to JADR. The project leading to these results also received funding from “la Caixa” Foundation (ID 100010434) under the agreement LCF/PR/HR19/52160007 and María de Maeztu Unit of Excellence (Institute of Neurosciences, University of Barcelona) MDM-2017-0729 (MCINN) to JADR. L.L. is supported by a fellowship from the FPU Programme of MECD (FPU15/02705).

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Authors and Affiliations

  1. Molecular and Cellular Neurobiotechnology, Institute for Bioengineering of Catalonia (IBEC), Scientific Park of Barcelona, The Barcelona Institute for Science and Technology (BIST), Baldiri and Reixac 15-21, 08028, Barcelona, Spain

    Laia Lidón, Jose A. del Rio & Rosalina Gavín

  2. Department of Cell Biology, Physiology and Immunology, Faculty of Biology, University of Barcelona, Av. Diagonal 643, 08028, Barcelona, Spain

    Laia Lidón, Jose A. del Rio & Rosalina Gavín

  3. Network Centre of Biomedical Research of Neurodegenerative Diseases (CIBERNED), Institute of Health Carlos III, Ministry of Economy and Competitiveness, Madrid, Spain

    Laia Lidón, Isidro Ferrer, Félix Hernández, Jesús Ávila, Jose A. del Rio & Rosalina Gavín

  4. Institute of Neuroscience, University of Barcelona, Barcelona, Spain

    Laia Lidón, Isidro Ferrer, Jose A. del Rio & Rosalina Gavín

  5. Laboratory of Histology, Neuroanatomy and Neuropathology, UNI (ULB Neuroscience Institute), Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium

    Cristina Vergara

  6. Department of Pathology and Experimental Therapeutics, University of Barcelona, Barcelona, Spain

    Isidro Ferrer

  7. Bellvitge University Hospital, IDIBELL (Bellvitge Biomedical Research Centre), Barcelona, Spain

    Isidro Ferrer

  8. Center of Molecular Biology “Severo Ochoa” (CSIC-UAM), Madrid, Spain

    Félix Hernández & Jesús Ávila

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  1. Laia Lidón
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  2. Cristina Vergara
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  4. Félix Hernández
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Correspondence to Jose A. del Rio or Rosalina Gavín.

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All experiments were performed under the guidelines and protocols of the Ethical Committee for Animal Experimentation (CEEA) at the University of Barcelona, and the protocol for the use of animals in this study was reviewed and approved by the CEEA at the University of Barcelona (CEEA approval# 276/16).

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Electronic supplementary material

Supplementary Fig. 1

Quantification and statistical processing of changes in PrPC levels by ADDLs or tau. (a-c) Histograms showing the densitometry analysis of PrPC expression in a. Primary cortical cultures from WT mice treated with either ADDL or vehicle alone (n = 4 each case). b. Extracts from hippocampal sections of ADDL-injected mice (n = 5). c. C17.2 culture transfected with mock or human 0N3R tau or 2N4R tau expression plasmids (pSG5, pSGT30, or pSGT43, respectively), (n = 3 each case). d. CTCF values derived from immunofluorescence microphotographs of PrPC expression in tau-GFP mouse (TgTP6.3) cortical cultures. Bars in all cases represent the mean ± SD of different samples analyzed in each case. Asterisks indicate statistical differences between groups and controls considering ****p < 0.0001, ***p < 0.001, **p < 0.01, and *p < 0.05 (t-test). (JPG 2037 kb)

Supplementary Fig. 2

PrPC levels remain constant in tau knockout mice after ADDLs treatment. (a-d) Western blot analysis using total tau antibody (monoclonal Tau5) in parallel with anti-PrPC antibody (monoclonal 6H4) in each case. Actin was used as control loading protein. Primary cortical cultures from WT and Mapt−/− mice at 7 DIV were treated with either ADDL or vehicle alone (n = 2 each case). (JPG 70 kb)

Supplementary Fig. 3

PrPC expression in HEK293 cells. Western blot analysis using anti-PrPC monoclonal antibody (6H4) shows detectable levels of the protein at 2 DIV. (JPG 31 kb)

Supplementary Fig. 4

Functional analysis of the PRNP promoter in HEK293 cells after Bcl-2 transfection. a. Bars represent the mean ± SD of relative light units (RLU) obtained from one experiment performed in triplicate. b. Western blot analysis showing Bcl-2 levels after transfection in HEK293 lysates. Actin was used as control loading protein. (JPG 1925 kb)

Supplementary Fig. 5

Functional analysis of the PRNP promoter in C17.2 cells after H2O2 treatment and tau transfection. a. Bars represent the mean ± SD of relative light units (RLU) standardized to untreated cells (Control) obtained from one experiment performed in triplicate. Groups were compared as follows: H2O2 vs control and tau vs mock transfection. b. Western blot analysis showing the two tau isoforms (tau3R and tau 4R) after 0N3R tau and 2N4R tau transfection in C17.2 lysates. Actin was used as control loading protein. Differences between groups (H2O2 vs control or tau vs mock transfection) were considered statistically significant at ***p < 0.001 and *p < 0.05 (t-test). (JPG 2022 kb)

Supplementary Fig. 6

Direct correlation between the amount of tau derived from P301S mice and PRNP promoter activity. a. Western blot analysis using total tau antibody (Tau5) of mouse brain fractions used in functional analysis of PRNP promoter: soluble brain extracts from 2 and 3 months old P301S mice compared to 9 months old P301S and WT mice. Actin was used as control loading protein. b. Histograms illustrating the promoter activity of HEK293 cells treated with brain extract from 2, 3 and 9 months old P301S mice and compared to untreated cells (Control) from one experiment performed in triplicate. Data are shown as mean ± SD. (JPG 2037 kb)

Supplementary Fig. 7

Recombinant tau variants used to perform functional analysis of PRNP promoter after western blot analysis. Both phosphorylated and non-phosphorylated species were immunoblotted with total tau antibody (Tau5) after oligomeric tau (O-tau/O-ptau) and fibrillary tau (F-tau/F-ptau) formation, respectively. (JPG 80 kb)

Supplementary Fig. 8

Functional analysis of PRNP activity using site-directed mutagenesis of AP-1 and Sp1 binding sites after P301S brain extract treatment. (a, b) Quantitative RLU obtained for each experimental group in full-length PRNP promoter construct (PRNP-pGL2basic) vs AP-1 (a) and Sp1 (b) deleted mutants and from n = 3 experiments performed in triplicate. Data are shown as mean ± SD and differences between groups were considered statistically significant at ***p < 0.001, **p < 0.01, and *p < 0.05 (t-test). (JPG 2155 kb)

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Lidón, L., Vergara, C., Ferrer, I. et al. Tau Protein as a New Regulator of Cellular Prion Protein Transcription. Mol Neurobiol 57, 4170–4186 (2020). https://doi.org/10.1007/s12035-020-02025-x

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  • DOI: https://doi.org/10.1007/s12035-020-02025-x

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