Low doses of bioherbicide favour prion aggregation and propagation in vivo

Public concerns over the use of synthetic pesticides are growing since many studies have shown their impact on human health. A new environmental movement in occidental countries promoting an organic agriculture favours the rebirth of botanical pesticides. These products confer an effective alternative to chemical pesticides such as glyphosate. Among the biopesticides, the α-terthienyls found in the roots of Tagetes species, are powerful broad-spectrum pesticides. We found that an α-terthienyl analogue with herbicidal properties, called A6, triggers resistant SDS oligomers of the pathogenic prion protein PrP(Sc) (rSDS-PrP(Sc)) in cells. Our main question is to determine if we can induce those rSDS-PrP(Sc) oligomers in vitro and in vivo, and their impact on prion aggregation and propagation. Using wild-type mice challenged with prions, we showed that A6 accelerates or slows down prion disease depending on the concentration used. At 5 mg/kg, A6 is worsening the pathology with a faster accumulation of PrP(Sc), reminiscent to soluble toxic rSDS-PrP(Sc) oligomers. In contrast, at 10 and 20 mg/kg of A6, prion disease occurred later, with less PrP(Sc) deposits and with rSDS-PrP(Sc) oligomers in the brain reminiscent to non-toxic aggregates. Our results are bringing new openings regarding the impact of biopesticides in prion and prion-like diseases.