Loss of PIKfyve drives the spongiform degeneration in prion diseases

Brain-matter vacuolation is a defining trait of all prion diseases, yet its cause is unknown. Here we report that prion infection and prion-mimetic antibodies deplete the phosphatidylinositol kinase PIKfyve in mouse brains, cultured cells, organotypic brain slices, and in brains of Creutzfeldt-Jakob Disease victims. We found that PIKfyve, an inositol kinase involved endolysosomal maturation, is acylated by zDHHC9 and zDHHC21, whose juxtavesicular topology is disturbed by prion infection, resulting in PIKfyve deacylation and destabilization. A protracted unfolded protein response (UPR), typical of prion diseases, also induced PIKfyve deacylation and degradation. Conversely, UPR antagonists restored PIKfyve levels in prion-infected cells. Overexpression of zDHHC9 and zDHHC21, administration of the antiprion polythiophene LIN5044, or supplementation with the PIKfyve reaction product PI(3,5)P2, suppressed prion-induced vacuolation. Thus, PIKfyve emerges as a central mediator of vacuolation and neurotoxicity in prion diseases.