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Updated: Jun 22, 2026
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Investigating the Spreading and Toxicity of Prion-like Proteins Using the Metazoan Model Organism C. elegans
Published on: January 8, 2015
Selective processing and metabolism of disease-causing mutant prion proteins
Aarthi Ashok1, Ramanujan S Hegde
1Cell Biology and Metabolism Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, United States of America.
Plos Pathogens
|June 23, 2009
Summary
Genetic prion diseases involve misfolded prion proteins (PrP). This study reveals a novel pathway where misfolded PrP mutants traffic to lysosomes for degradation, potentially explaining spontaneous PrP(Sc) generation.
Area of Science:
- Neurobiology
- Cell Biology
- Molecular Biology
Background:
- Prion diseases are fatal neurodegenerative disorders linked to misfolded cellular prion protein (PrP(C)).
- Genetic mutations in PrP's C-terminal domain are suspected to promote misfolded conformers (PrP(Sc)) causing neuronal death.
- Understanding PrP quality control is crucial for mechanistic insights into prion diseases.
Purpose of the Study:
- To investigate the biosynthesis, trafficking, and degradation of genetic prion disease-associated PrP mutants.
- To elucidate the quality control pathways involved in managing aberrant PrP conformers.
- To identify cellular mechanisms underlying spontaneous PrP(Sc) generation in familial prion diseases.
Main Methods:
- Comparative analysis of PrP mutant biosynthesis, trafficking, and metabolism.
- Quantitative imaging and biochemical assays to characterize misfolded PrP subpopulations.
- Investigation of protein quality control, ER-associated degradation, and lysosomal pathways.
Main Results:
- Identified a misfolded PrP subpopulation with detergent insolubility, reduced cell surface presence, and incomplete glycosylation.
- Demonstrated that misfolded PrP mutants bypass ER quality control and ER-associated degradation.
- Revealed selective trafficking of misfolded PrP to acidic compartments (lysosomes) via a pathway dependent on the globular domain and an N-terminal lysine motif.
Conclusions:
- Defined a novel, shared trafficking and degradation pathway for multiple disease-causing PrP mutants.
- This mutant-selective lysosomal trafficking pathway may provide a cell biological basis for spontaneous PrP(Sc) generation in familial prion diseases.
- The acidic lysosomal environment's role in PrP(C) to PrP(Sc) conversion is highlighted by this finding.
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