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Communication dans un congrès

Endogenous proteolytic cleavage of disease-associated prion protein to produce C2 fragments is strongly cell- and tissue-dependent

Abstract : Abnormally folded prion protein (PrPSc) accumulating in the nervous and lymphoid tissues of prion-infected individuals can be naturally cleaved to generate a N-terminally truncated fragment called C2. Cell cultures permissive to infection provide useful models in which biochemical events associated with prion replication can be studied. Rov and MovS cell lines, primary cultured cerebellar granule neurons (CGN) and astrocytes (CAS) established from ovine PrP transgenic mice tg338, in which natural sheep scrapie agent can be propagated, and CAD neuronal cell line susceptible to mouse-adapted scrapie strains. We examined the N-terminal processing of PrPSc in such cell models and in mouse tissues. Using a combination of cell and biochemical approaches we showed that: i) the efficiency of trimming varies considerably depending on the infected cell or tissue. In primary neurons and in brain tissue, PrPSc accumulated essentially as full length (FL) species, whereas nearly exhaustive trimming occurred in Rov and MovS cells, and in spleen tissue. An intermediate situation, i.e. accumulation in amounts of both C2 and FL PrPSc was observed in primary astrocytes and CAD cells. ii) while C2 is generally considered to be the counterpart of PrPSc PK-resistant core, N-termini of in vivo and in vitro cleaved fragments can actually differ, as evidenced by a different reactivity toward antibody Pc248 that recognizes the octarepeat domain with very high affinity. iii) impairment of lysosomal activity suffices to block C2 formation in Rov and CAD cells, arguing for primary involvement of hydrolases of the acidic cell compartment; however, fairly efficient propagation of prions can occur in subpassaged cultures under conditions of C2 inhibition. Our findings bring new information on the natural, cell-dependent processing of PrPSc molecules, which has substantial implications in terms of prion cell biology, PrPSc molecular analysis and subtyping of TSE agents.
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Communication dans un congrès
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https://hal.inrae.fr/hal-02756698
Déposant : Migration Prodinra <>
Soumis le : mercredi 3 juin 2020 - 23:15:40
Dernière modification le : vendredi 12 juin 2020 - 10:43:26

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  • HAL Id : hal-02756698, version 1
  • PRODINRA : 147392

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Mohammed Moudjou, Michel Dron, Jerome Chapuis, Julie Bernard, Muhammad Khalid Salamat, et al.. Endogenous proteolytic cleavage of disease-associated prion protein to produce C2 fragments is strongly cell- and tissue-dependent. Prion 2009, Sep 2009, Chalkidiki, Greece. ⟨hal-02756698⟩

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