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Identification of two prion protein regions that modify scrapie incubation time

S Supattapone1, T Muramoto, G Legname

  • 1Institute for Neurodegenerative Diseases, University of California, San Francisco, California 94143, USA.

Journal of Virology
|January 11, 2001
PubMed

Insights

Prion protein (PrP) structure impacts prion disease. Transgenic mice experiments show that the N-terminus of mouse PrP and a specific chimeric region influence how efficiently prions propagate, affecting disease incubation times.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Prion diseases are fatal neurodegenerative disorders caused by misfolded prion proteins (PrP).
  • The structure of PrP is critical for its conversion into a pathogenic form and subsequent disease transmission.
  • Understanding the molecular determinants of prion propagation is essential for developing therapeutic strategies.

Purpose of the Study:

  • To investigate how different prion protein (PrP) structures influence prion disease incubation times.
  • To determine the role of the N-terminus of mouse PrP and specific chimeric regions in prion propagation efficiency.
  • To explore the impact of PrP sequence variations on susceptibility to different prion strains.

Main Methods:

  • Prion transmission experiments were conducted in transgenic (Tg) mice expressing various PrP constructs.
  • Mice were inoculated with Rocky Mountain Laboratory (RML) murine prions and other prion strains.
  • Scrapie incubation times were measured and compared across different Tg mouse lines.

Main Results:

  • Tg mice expressing wild-type mouse PrP (Tg(MoPrP)4053) showed shorter incubation times (approx. 50 days) compared to those with chimeric (Tg(MHM2)294/Prnp(0/0)) or truncated PrP (Tg(MoPrP, Delta23-88)9949/Prnp(0/0)).
  • Similar incubation times were observed across different mouse lines when inoculated with various prion strains, ruling out sequence-dependent transmission barriers.
  • Tg(MHM2)294/Prnp(0/0) mice exhibited prolonged incubation times with multiple prion strains, indicating a significant role of the MHM2 PrP region.

Conclusions:

  • The N-terminus of mouse PrP and the chimeric region of MHM2 PrP (residues 108-111) are key determinants of prion propagation efficiency.
  • These structural elements significantly influence the incubation period of prion diseases.
  • The findings provide crucial insights into the molecular mechanisms underlying prion pathogenesis and transmission barriers.

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