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Updated: Oct 27, 2025
Investigating the Spreading and Toxicity of Prion-like Proteins Using the Metazoan Model Organism C. elegans
Published on: January 8, 2015
Loss of PIKfyve drives the spongiform degeneration in prion diseases
Asvin K K Lakkaraju1, Karl Frontzek1, Emina Lemes1
1Institute of Neuropathology, University of Zurich, Zürich, Switzerland.
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.
Insights
Prion diseases cause brain vacuolation by depleting PIKfyve, a kinase controlling endolysosomal maturation. Restoring PIKfyve levels or function suppressed vacuolation and neurotoxicity in prion disease models.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Brain-matter vacuolation is a hallmark of prion diseases, but its underlying cause remains unclear.
- Prion diseases are characterized by neurodegeneration and the accumulation of misfolded prion proteins.
- Endolysosomal pathway dysfunction is implicated in various neurodegenerative disorders.
Purpose of the Study:
- To investigate the molecular mechanisms driving brain-matter vacuolation in prion diseases.
- To identify key cellular players involved in prion-induced neurotoxicity.
- To explore potential therapeutic targets for prion diseases.
Main Methods:
- Analysis of PIKfyve levels in mouse brains, cultured cells, organotypic brain slices, and human Creutzfeldt-Jakob disease brains.
- Investigating the role of acyltransferases zDHHC9 and zDHHC21 in PIKfyve regulation.
- Assessing the impact of unfolded protein response (UPR) on PIKfyve stability.
- Evaluating the efficacy of interventions like zDHHC9/zDHHC21 overexpression, LIN5044 administration, and PI(3,5)P2 supplementation in prion models.
Main Results:
- Prion infection and related antibodies deplete PIKfyve, a crucial kinase for endolysosomal maturation.
- Prion infection disrupts zDHHC9 and zDHHC21 topology, leading to PIKfyve deacylation and degradation.
- Prolonged UPR in prion diseases also causes PIKfyve deacylation and degradation; UPR antagonists restore PIKfyve levels.
- Overexpressing zDHHC9/zDHHC21, using LIN5044, or supplementing PI(3,5)P2 suppressed vacuolation and restored lysosomal homeostasis.
Conclusions:
- PIKfyve depletion is a central mechanism underlying vacuolation and neurotoxicity in prion diseases.
- Targeting PIKfyve regulation, zDHHC acyltransferases, or UPR pathways may offer therapeutic strategies for prion diseases.
- Restoring PIKfyve levels and lysosomal homeostasis is crucial for mitigating prion disease pathology.
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