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Alkylating antitumor drug mechlorethamine conceals a structured PrP domain and inhibits in vitro prion amplification
Xiaochen Zhou1, Hao Bi, Justin Wong
1Department of Pathology, National Prion Disease Pathology Surveillance Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
Abstract:
Prion diseases are a group of incurable transmissible neurodegenerative disorders. The key molecular event in the pathogenesis of prion diseases is the conversion of the cellular prion protein (PrP(C)) into its pathological isoform (PrP(Sc)), accompanied by a conformational transition of α-helix into β-sheet structure involving the structured α-helix 1 domain from residues 144-154 of the protein (PrP144-154). Blocking the accessibility of PrP144-152 with anti-PrP antibody 6H4 was found to prevent PrP conversion and even to cure prion infection in cell models ( Enari et al. 2001 ). Previously, Yuan et al. (2005 ) demonstrated that the reduction and alkylation of PrP induced concealment of the 6H4 epitope. This study examined the ability of mechlorethamine (MCT), an alkylating antitumor drug, to conceal the 6H4 epitope and block PrP conversion in the presence of a reducing reagent. Mechlorethamine treatment significantly decreased in vitro amplification of PrP(Sc) in the highly efficient protein misfolding cyclic amplification system. Our findings suggest that MCT may serve as a potential therapeutic agent for prion diseases.
Insights
Mechlorethamine (MCT), an alkylating drug, conceals a key prion protein region, blocking its pathological conversion. This suggests MCT could be a potential therapeutic for incurable prion diseases.
Area of Science:
- Neurodegenerative diseases
- Prion protein misfolding
- Drug discovery
Background:
- Prion diseases are fatal neurodegenerative disorders caused by misfolded prion proteins (PrPSc).
- The conversion of cellular PrP (PrPC) to PrPSc involves a conformational change in the PrP144-154 region.
- Antibody 6H4 blocks PrP conversion by targeting PrP144-152, suggesting this region's accessibility is crucial.
Purpose of the Study:
- To investigate if mechlorethamine (MCT), an alkylating agent, can conceal the 6H4 epitope and inhibit PrP conversion.
- To evaluate MCT's potential as a therapeutic agent for prion diseases.
Main Methods:
- Treatment of prion protein with mechlorethamine (MCT) and a reducing reagent.
- Assessing the concealment of the 6H4 epitope.
- Measuring PrPSc amplification using the protein misfolding cyclic amplification (PMCA) system.
Main Results:
- Mechlorethamine treatment effectively concealed the 6H4 epitope on the prion protein.
- MCT significantly reduced in vitro amplification of PrPSc in the PMCA system.
- The findings indicate MCT interferes with the prion conversion process.
Conclusions:
- Mechlorethamine's ability to block PrP conversion suggests its therapeutic potential for prion diseases.
- Targeting the PrP144-154 region with agents like MCT offers a promising strategy for prion disease treatment.
