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 acyltransferases 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 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 and restored lysosomal homeostasis. Thus, PIKfyve emerges as a central mediator of vacuolation and neurotoxicity in prion diseases.
Highlights
The self-sustaining recruitment of the cellular prion protein PrPC into its aggregated conformer PrPSc is the basis of prion transmissibility and neuroinvasion
We found that PIKfyve is acylated by the acyltransferases 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 transcription factor EB (TFEB)-dependent lysosomal enzymes
Through multiple lines of evidence, we show that PIKfyve depletion is a universal feature of prion pathology
Summary
The self-sustaining recruitment of the cellular prion protein PrPC into its aggregated conformer PrPSc is the basis of prion transmissibility and neuroinvasion. The ablation of PrPC prevents prion propagation (Bueler et al, 1993) and toxicity (Brandner et al, 1996). While these phenomena have been extensively studied, little is known about how PrPSc leads to neurodegeneration. The examination of prion-infected human, ruminant, and rodent brains invariably reveals prominent intracellular vacuolation conferring a foamy appearance (spongiosis) to brain tissue. The ubiquity of spongiosis in prion diseases suggests that it is intimately linked to the mechanism of disease. Little is known about the molecular drivers of spongiogenesis (Aguzzi et al, 2008)
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