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 phosphoinositide kinase PIKfyve-which controls endolysosomal maturation-from mouse brains, cultured cells, organotypic brain slices, and brains of Creutzfeldt-Jakob disease victims. We found that PIKfyve is acylated by the acyltransferases zDHHC9 and zDHHC21, whose...