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

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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.

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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.

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Author notes

  1. Caterina Peggion and Roberto Stella contributed equally to this work.

Authors and Affiliations

  1. Department of Biomedical Sciences, University of Padova, 35131, Padova, Italy

    Caterina Peggion, Giorgio Arrigoni, Cinzia Franchin, Maria Catia Sorgato & Alessandro Bertoli

  2. Department of Chemistry, Istituto Zooprofilattico Sperimentale delle Venezie, 35020, Legnaro, PD, Italy

    Roberto Stella & Giancarlo Biancotto

  3. Department of Biology, University of Padova, 35131, Padova, Italy

    Francesco Chemello & Stefano Cagnin

  4. CNR—Neuroscience Institute, University of Padova, 35131, Padova, Italy

    Maria Lina Massimino & Maria Catia Sorgato

  5. Proteomics Center, University of Padova and Azienda Ospedaliera di Padova, 35129, Padova, Italy

    Giorgio Arrigoni & Cinzia Franchin

  6. Padova Neuroscience Center, University of Padova, 35131, Padova, Italy

    Alessandro Bertoli

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  1. Caterina Peggion
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Correspondence to Caterina Peggion or Alessandro Bertoli.

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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.

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Peggion, C., Stella, R., Chemello, F. et al. The Prion Protein Regulates Synaptic Transmission by Controlling the Expression of Proteins Key to Synaptic Vesicle Recycling and Exocytosis. Mol Neurobiol 56, 3420–3436 (2019). https://doi.org/10.1007/s12035-018-1293-4

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