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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
An N-terminal polybasic domain and cell surface localization are required for mutant prion protein toxicity
Isaac H Solomon1, Natasha Khatri, Emiliano Biasini
1Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
The Journal of Biological Chemistry
|March 10, 2011
Summary
Altered cellular prion protein (PrP(C)) activity contributes to neurotoxicity. This study identifies key PrP sequence domains and plasma membrane localization essential for toxic activity, potentially linking normal PrP(C) function to prion disease pathogenesis.
Area of Science:
- Neuroscience
- Molecular Biology
- Prion Disease Research
Background:
- Prion diseases are linked to the cellular prion protein (PrP(C)) but its normal function and role in neurotoxicity are poorly understood.
- Investigating PrP(C) function is challenging due to the lack of functional assays and the obscure nature of its physiological role.
- Previous work showed PrP lacking residues 105-125 (Δ105-125 PrP) exhibits ionic currents and drug hypersensitivity.
Purpose of the Study:
- To investigate how alterations in PrP sequence and cellular localization affect its functional activity.
- To utilize novel cell culture assays to probe the mechanisms of PrP-mediated neurotoxicity.
- To identify specific PrP domains critical for both normal function and conversion to pathogenic forms.
Main Methods:
- Development and application of cell culture assays measuring spontaneous ionic currents and drug hypersensitivity.
- Systematic deletion and point mutation analysis of the PrP sequence.
- Assessment of PrP cellular localization, particularly at the plasma membrane.
- Correlation of identified functional domains with PrP(Sc) formation.
Main Results:
- Toxic activity of Δ105-125 PrP is dependent on its localization to the plasma membrane.
- A polybasic amino acid segment at the N terminus of PrP is crucial for its toxic activity.
- Various central region deletions and disease-associated point mutations in PrP also confer toxic activity.
- Identified sequence domains are critical for both PrP(C) functional activity and PrP(Sc) formation.
Conclusions:
- PrP(C) functional activity, particularly its toxic potential, is regulated by specific sequence domains and proper cellular localization.
- Common structural features may underlie both the physiological function of PrP(C) and its conversion into the pathogenic PrP(Sc) form.
- These findings provide novel insights into prion neurotoxicity mechanisms and potential therapeutic targets.
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