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The Prion Protein Regulates Synaptic Transmission by Controlling the Expression of Proteins Key to Synaptic Vesicle Recycling and Exocytosis

  • Caterina Peggion
  • Roberto Stella
  • Francesco Chemello
  • Maria Lina Massimino
  • Giorgio Arrigoni
  • Stefano Cagnin
  • Giancarlo Biancotto
  • Cinzia Franchin
  • Maria Catia Sorgato
  • Alessandro Bertoli
Article

Abstract

The cellular prion protein (PrPC), whose misfolded conformers are implicated in prion diseases, localizes to both the presynaptic membrane and postsynaptic density. To explore possible molecular contributions of PrPC to synaptic transmission, we utilized a mass spectrometry approach to quantify the release of glutamate from primary cerebellar granule neurons (CGN) expressing, or deprived of (PrP-KO), PrPC, following a depolarizing stimulus. Under the same conditions, we also tracked recycling of synaptic vesicles (SVs) in the two neuronal populations. We found that in PrP-KO CGN these processes decreased by 40 and 60%, respectively, compared to PrPC-expressing neurons. Unbiased quantitative mass spectrometry was then employed to compare the whole proteome of CGN with the two PrP genotypes. This approach allowed us to assess that, relative to the PrPC-expressing counterpart, the absence of PrPC modified the protein expression profile, including diminution of some components of SV recycling and fusion machinery. Subsequent quantitative RT-PCR closely reproduced proteomic data, indicating that PrPC is committed to ensuring optimal synaptic transmission by regulating genes involved in SV dynamics and neurotransmitter release. These novel molecular and cellular aspects of PrPC add insight into the underlying mechanisms for synaptic dysfunctions occurring in neurodegenerative disorders in which a compromised PrPC is likely to intervene.

Keywords

Prion protein Neurotransmission Synaptic vesicle Mass spectrometry Selected reaction monitoring Gene expression 

Notes

Acknowledgements

Authors are grateful to Drs. Domenico Azarnia Tehran and Fiorella Tonello for helpful suggestions on the synaptic vesicle recycling assay, and to Dr. Cesare Montecucco for kindly providing us with the needed serotype of botulinum toxin. This work was supported by the University of Padova (PRAT CPDA158035 to A.B. and CPDA139317 to S.C.). C.P. was supported by a grant to G.A. (CPDR159477/15). Authors also acknowledge the Cassa di Risparmio di Padova e Rovigo (Cariparo) Holding for funding acquisition of the LTQ-Orbitrap XL mass spectrometer.

Compliance with Ethical Standards

All experimental procedures and animal care protocols were approved by the Italian Ministry of Health (authorization no. 743/2017-PR) and by the Ethical Committee for animal care and use of the University of Padova.

Conflict of Interest

The authors declare no potential conflict of interest.

Supplementary material

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Copyright information

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

Authors and Affiliations

  1. 1.Department of Biomedical SciencesUniversity of PadovaPadovaItaly
  2. 2.Department of ChemistryIstituto Zooprofilattico Sperimentale delle VenezieLegnaroItaly
  3. 3.Department of BiologyUniversity of PadovaPadovaItaly
  4. 4.CNR—Neuroscience InstituteUniversity of PadovaPadovaItaly
  5. 5.Proteomics CenterUniversity of Padova and Azienda Ospedaliera di PadovaPadovaItaly
  6. 6.Padova Neuroscience CenterUniversity of PadovaPadovaItaly

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