Prion diseases are caused by the propagation of PrP Sc , the pathological conformation of the PrP C prion protein. The molecular mechanisms underlying PrP Sc propagation are still unsolved and no therapeutic solution is currently available. We thus sought to identify new anti-prion molecules and found that flunarizine inhibited PrP Sc propagation in cell culture and significantly prolonged survival of prion-infected mice. Using an in silico therapeutic repositioning approach based on similarities with flunarizine chemical structure, we tested azelastine, duloxetine, ebastine, loperamide and metixene and showed that they all have an anti-prion activity. Like flunarizine, these marketed drugs reduced PrP Sc propagation in cell culture and in mouse cerebellum organotypic slice culture, and inhibited the protein folding activity of the ribosome (PFAR). Strikingly, some of these drugs were also able to alleviate phenotypes due to PABPN1 nuclear aggregation in cell and Drosophila models of oculopharyngeal muscular dystrophy (OPMD). These data emphasize the therapeutic potential of anti-PFAR drugs for neurodegenerative and neuromuscular proteinopathies.

Rift Valley fever virus (RVFV) is a highly pathogenic zoonotic arbovirus endemic in many African countries and the Arabian Peninsula. Animal infections cause high rates of mortality and abortion among sheep, goats and cattle. In humans, an estimated 1-2% of RVFV infections result in severe disease (encephalitis, hepatitis, retinitis) with a high rate of lethality when associated to hemorrhagic fever. RVFV's NSs protein, which is RVFV's main factor of virulence, counteracts the host innate antiviral response favoring viral replication and spread. However, the mechanisms underlying RVFV-induced cytopathic effects and the role of NSs in these alterations remain for the most undeciphered. In this work we have analyzed the effects of NSs expression on actin cytoskeleton while conducting infections with the NSs expressing virulent (ZH548) and attenuated (MP12) strains of RVFV and the non-NSs expressing avirulent (ZH548ΔNSs) strain as well as after the ectopic expression of NSs. In macrophages, fibroblasts and hepatocytes NSs expression prevented the up-regulation of Abl2 (a major regulator of actin cytoskeleton) expression otherwise induced by avirulent infections and identified here as part of the antiviral response. The presence of NSs was also linked to and increased mobility of ZH548- as compared to ZH548ΔNSs-infected fibroblasts and to strong changes in cell morphology in non-migrating hepatocytes with reduction of lamellipodia, cell spreading and dissolution of adherens junctions reminiscent of ZH548-induced cytopathic effects observed in vivo. Finally, we show evidence of the presence of NSs within long actin-rich structures associated to NSs dissemination from NSs expressing towards non-NSs expressing cells. Importance. Rift Valley fever virus (RVFV) is a dangerous human and animal pathogen that was ranked in 2018 by the World Health Organization among the eight pathogens of most concern likely to cause wide epidemics in the near future for which there is no, or insufficient, countermeasures. The interest of this work resides in the fact that it addresses the question of the mechanisms underlying RVFV-induced cytopathic effects that participate in RVFV's pathogenicity. We demonstrate here that RVFV targets cell adhesion and actin cytoskeleton at the transcriptional and cellular level, affecting cell mobility and inducing cell shape collapse alongside with distortion of cell-cell adhesion. All these effects are susceptible to participate in RVFV-induced pathogenicity, facilitate virulent RVFV dissemination and thus constitute interesting potential targets in future development of antiviral therapeutic strategies that in the case of RVFV, as several other emerging arboviruses, are presently lacking.