Loss of PIKfyve drives the spongiform degeneration in prion diseases.

ABSTRACT: 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 acyl transferases zDHHC9 and zDHHC21, whose juxtavesicular topology is disturbed by prion infection, resulting in PIKfyve deacylation and rapid degradation, as well as endolysosomal hypertrophy and activation of TFEB-dependent lysosomal enzymes. A protracted unfolded protein response (UPR), typical of prion diseases, also induced PIKfyve deacylation and degradation. Conversely, UPR antagonists resto

SUBMITTER: Dr. Asvin, KK Lakkaraju 

PROVIDER: S-SCDT-EMM-2021-14714P | biostudies-other |

REPOSITORIES: biostudies-other