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Epigenetic Control of the Notch and Eph Signaling Pathways by the Prion Protein: Implications for Prion Diseases

  • Théo Z. Hirsch
  • Séverine Martin-Lannerée
  • Fabienne Reine
  • Julia Hernandez-Rapp
  • Laetitia Herzog
  • Michel Dron
  • Nicolas Privat
  • Bruno Passet
  • Sophie Halliez
  • Ana Villa-Diaz
  • Caroline Lacroux
  • Victor Klein
  • Stéphane Haïk
  • Olivier Andréoletti
  • Juan-Maria Torres
  • Jean-Luc Vilotte
  • Vincent Béringue
  • Sophie Mouillet-Richard
Article

Abstract

Among the ever-growing number of self-replicating proteins involved in neurodegenerative diseases, the prion protein PrP remains the most infamous for its central role in transmissible spongiform encephalopathies (TSEs). In these diseases, pathogenic prions propagate through a seeding mechanism, where normal PrPC molecules are converted into abnormally folded scrapie isoforms termed PrPSc. Since its discovery over 30 years ago, much advance has contributed to define the host-encoded cellular prion protein PrPC as a critical relay of prion-induced neuronal cell demise. A current consensual view is that the conversion of PrPC into PrPSc in neuronal cells diverts the former from its normal function with subsequent molecular alterations affecting synaptic plasticity. Here, we report that prion infection is associated with reduced expression of key effectors of the Notch pathway in vitro and in vivo, recapitulating changes fostered by the absence of PrPC. We further show that both prion infection and PrPC depletion promote drastic alterations in the expression of a defined set of Eph receptors and their ephrin ligands, which represent important players in synaptic function. Our data indicate that defects in the Notch and Eph axes can be mitigated in response to histone deacetylase inhibition in PrPC-depleted as well as prion-infected cells. We thus conclude that infectious prions cause a loss-of-function phenotype with respect to Notch and Eph signaling and that these alterations are sustained by epigenetic mechanisms.

Keywords

Prion infection Cellular prion protein Notch Eph HDAC 

Notes

Funding

This work was supported by funds from INSERM to S.M.-R. T.Z.H. was supported by a fellowship from Fondation pour la Recherche Médicale. VB, FR, and LH were financially supported by grants from the French Medical Research Foundation (FRM; Equipe FRM DEQ20150331689).

Compliance with Ethical Standards

Competing Interests

The authors declare that they have no competing interest.

Supplementary material

12035_2018_1193_MOESM1_ESM.pdf (961 kb)
Fig S1 PrPres deposition in the brains of tga20 mice inoculated with Fk-1C11 cells. Representative histoblots of antero-posterior coronal brain sections (12F10 antibody) at the level of the septum (i), hippocampus (ii), midbrain (iii-iv) and brainstem (v-vii) are shown. Scale bar, 1 mm. (PDF 961 kb)
12035_2018_1193_MOESM2_ESM.pdf (73 kb)
Fig S2 The Notch and Eph/ephrin networks are affected in total brain of mice infected with 139A prions. (a-b) Quantitative RT-PCR analysis of the expression of genes encoding Jag1, Jag2 (left panel), Notch1, Notch2, Notch3 (middle panel) and the Notch target genes Hes5 and Blbp (right panel) (a) the EphA receptor family (top left panel), EphB receptor family (top right panel), the ephrinA ligand family (bottom left panel) and ephrinB ligand family (bottom right panel) (b) in tga20 mice infected with the 139A prion strain vs. control tga20 mice (total brain). Results are expressed as means ± s.e.m. of n = 5 to 6 mice * p < 0.05, ** p < 0.01, *** p < 0.001 versus control (Student’s t-test). (PDF 72 kb)
12035_2018_1193_MOESM3_ESM.pdf (1.6 mb)
Fig S3 Prion infection affects the Eph/ephrin network in the brainstem and the cerebellum. Quantitative RT-PCR analysis of the expression of genes of the EphA receptor family (top left panels), EphB receptor family (top right panels), ephrinA ligand family (bottom left panels) and ephrinB ligand family (bottom right panels) was performed in brainstem (a) or cerebellum (b) from mice inoculated with Fk-1C11 cells or control cells. Results are expressed as means ± s.e.m. of n = 5 mice. * p < 0.05, ** p < 0.01, *** p < 0.001 versus control (Student’s t-test). (PDF 1.64 mb)
12035_2018_1193_MOESM4_ESM.pdf (105 kb)
Fig S4 The Eph/ephrin network is affected in neurospheres devoid of PrPC and neural tubes from embryos lacking PrPC. Quantitative RT-PCR analysis of the expression of genes of the EphA receptor family (top left panel), EphB receptor family (top right panel), ephrinA ligand family (bottom left panel) and ephrinB ligand family (bottom right panel) was performed in Prnp−/− NSC versus their PrPC-expressing counterparts (a) or in dissected neural tubes from E10.5 Prnp−/− versus WT embryos (b). Results are expressed as means ± s.e.m. of n = 3 cell preparations (a) or n = 6 to 10 mice (b). * p < 0.05, ** p < 0.01, *** p < 0.001 versus control (Student’s t-test). Venn diagram and heatmap summary of the changes in Eph and ephrin expression in the 3 different models of PrPC depletion: PrPKD-1C11 cells, Prnp−/− neurospheres and neural tubes from E10.5 Prnp−/−, highlighting common impacts on the Eph network (c). (PDF 105 kb)
12035_2018_1193_MOESM5_ESM.pdf (230 kb)
Fig S5 PrPC depletion and prion infection share alterations in the Notch and Eph pathways. Venn diagram (a) and heatmap (b) summary of the changes in Notch, Jagged and Eph and ephrin expression upon PrPC depletion in vitro (PrPKD-1C11 cells) as compared to infection with Fk prions in vitro (Fk-1C11 cells) and in vivo (Fk-infected brain), highlighting common impacts of prion depletion and prion infection on the Notch and Eph networks. (PDF 229 kb)
12035_2018_1193_MOESM6_ESM.pdf (960 kb)
Fig S6 Impact of Notch pathway activation on the Eph network in PrPC-expressing cells. Quantitative RT-PCR analysis of the expression of genes of the EphA receptor family (top left panel), EphB receptor family (top right panel), ephrinA ligand family (bottom left panel) and ephrinB ligand family (bottom right panel) was performed in 1C11 cells exposed to recombinant Jagged1. Results are expressed as means ± s.e.m. of n = 2 independent duplicates of cell preparations. * p < 0.05, ** p < 0.01, *** p < 0.001 versus control (Student’s t-test). (PDF 960 kb)
12035_2018_1193_MOESM7_ESM.pdf (1.7 mb)
Fig S7 Inhibition of HDAC exerts a positive impact on Jagged1 and Notch1 in prioninfected 1C11 cells. (a-b) Immunoblot analysis (a) and corresponding quantification (b) of the protein levels of Jagged1 and Notch1 in Fk-1C11 exposed to VPA vs. control Fk-1C11 and 1C11 cells exposed to 2M2P. Results are expressed as means ± s.e.m. of n = 2 to 3 independent triplicates of cell preparations. ** p < 0.01 versus control 1C11-2M2P cells, # p < 0.05 ##, p < 0.01 versus Fk-1C11-2M2P cells (Student’s t-test). (PDF 1.65 mb)
12035_2018_1193_MOESM8_ESM.docx (116 kb)
Supplemental Table 1 (DOCX 116 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Théo Z. Hirsch
    • 1
    • 2
    • 3
  • Séverine Martin-Lannerée
    • 1
    • 2
  • Fabienne Reine
    • 4
  • Julia Hernandez-Rapp
    • 1
    • 2
    • 5
  • Laetitia Herzog
    • 4
  • Michel Dron
    • 4
  • Nicolas Privat
    • 6
    • 7
  • Bruno Passet
    • 8
  • Sophie Halliez
    • 4
    • 9
  • Ana Villa-Diaz
    • 10
  • Caroline Lacroux
    • 11
  • Victor Klein
    • 1
    • 2
  • Stéphane Haïk
    • 6
    • 7
  • Olivier Andréoletti
    • 11
  • Juan-Maria Torres
    • 10
  • Jean-Luc Vilotte
    • 8
  • Vincent Béringue
    • 6
  • Sophie Mouillet-Richard
    • 1
    • 2
  1. 1.INSERM UMR 1124ParisFrance
  2. 2.Université Paris DescartesParisFrance
  3. 3.INSERM U1162ParisFrance
  4. 4.INRA, Université Paris-Saclay, UR 892 Virologie Immunologie MoléculairesJouy-en-JosasFrance
  5. 5.Centre de Recherche du CHU de QuébecUniversité Laval, QuébecQuébecCanada
  6. 6.INSERM UMR 1127, CNRS UMR 7225ParisFrance
  7. 7.Institut du Cerveau et de la Moelle épinière, ICM, Inserm U 1127, CNRS UMR 7225Sorbonne UniversitéParisFrance
  8. 8.INRA UMR1313, Génétique Animale et Biologie IntégrativeJouy-en-JosasFrance
  9. 9.INSERM, UMR-S1172Lille UniversityLilleFrance
  10. 10.Centro de Investigación en Sanidad Animal-INIAMadridSpain
  11. 11.INRA-ENVT UMR 1225ToulouseFrance

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