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Updated: Jul 14, 2026
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High-throughput Screening for Protein-based Inheritance in S. cerevisiae
Published on: August 8, 2017
Prion protein repeat expansion results in increased aggregation and reveals phenotypic variability
Elizabeth M H Tank1, David A Harris, Amar A Desai
1Department of Cell Biology and Physiology, Washington University School of Medicine, Campus Box 8228, 660 S. Euclid Ave., St. Louis, MO 63110, USA.
Molecular and Cellular Biology
|June 6, 2007
Summary
Oligopeptide repeat expansion in prion protein (PrP) increases its flexibility and aggregation, potentially explaining varied symptoms in inherited prion diseases.
Area of Science:
- Neuroscience
- Biochemistry
- Genetics
Background:
- Mammalian prion diseases are fatal neurodegenerative disorders linked to the prion protein (PrP).
- Expansion of oligopeptide repeats (ORE) in PrP is associated with inherited prion diseases, often showing phenotypic variability.
- The precise mechanisms driving this variability are not fully understood.
Purpose of the Study:
- To investigate the influence of the PrP ORE on prion properties using chimeric yeast-mammalian prion proteins.
- To determine how ORE expansion affects prion aggregation, conformational flexibility, and conversion rates.
- To elucidate the role of ORE in the phenotypic variability of prion diseases.
Main Methods:
- Construction of chimeric yeast-mammalian prion proteins incorporating varying lengths of PrP ORE.
- Assessment of prion characteristics, including aggregation propensity and self-propagation, in yeast models.
- Analysis of conformational flexibility and phenotypic variation in chimeric proteins.
- Measurement of prion conversion rates in the presence and absence of other prions, such as [RNQ+].
Main Results:
- All chimeric proteins successfully maintained prion characteristics in yeast.
- The largest repeat expansion chimera showed a greater tendency for self-propagating aggregation.
- Repeat expansion significantly increased conformational flexibility, leading to enhanced phenotypic variation.
- Prion conversion rates increased in the repeat expansion chimera, but only when the [RNQ+] prion was present.
Conclusions:
- The PrP ORE enhances prion protein conformational flexibility, promoting diverse aggregate structures.
- Increased flexibility and varied aggregate formation contribute to the phenotypic variability observed in PrP repeat expansion diseases.
- Yeast models provide valuable insights into the molecular mechanisms underlying mammalian prion diseases.
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