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Identification and characterization of a novel mouse prion gene allele
Sarah E Lloyd1, Simon R Thompson, Jonathan A Beck
1MRC Prion Unit and Department of Neurodegenerative Disease, Institute of Neurology, University College, London, WC1N 3BG, UK.
Abstract:
The major determinant of prion disease incubation time in mice is thought to be the amino acid sequence of the prion protein. Two alleles of the mouse prion gene ( Prnp) have been described, where Prnp(a) (Leu-108, Thr-189) and Prnp(b) (Phe-108, Val-189) are associated with short and long incubation times, to defined prion strains, respectively. As part of a survey of inbred mouse lines, the prion gene open reading frame was sequenced and revealed a new allele, Prnp(c) (Phe-108, Thr-189), in the strain MAI/Pas. To study the influence of Prnp(c) independently of the MAI/Pas genetic background, we generated a congenic line in which Prnp(c) was bred onto the C57BL/6JOlaHsd background. Following intracerebral inoculation with Chandler/RML scrapie prions, the congenic mice showed an increased mean incubation time relative to C57BL/6JOlaHsd, of over 100 days. However, no differences were observed in the intensity and pattern of PrP immunoreactivity deposition or spongiosis. We conclude that the new allele, Prnp(c), modulates incubation time but not neuropathology and that the previous classification of mice into two distinct groups based on incubation time and Prnp genotype should now be revised.
Insights
A new prion protein gene allele (Prnp(c)) in mice significantly increases prion disease incubation time. This finding challenges existing classifications of prion disease susceptibility based on Prnp genotype.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Prion disease incubation time is primarily determined by prion protein (PrP) amino acid sequence.
- Two known mouse prion gene (Prnp) alleles, Prnp(a) and Prnp(b), correlate with short and long incubation periods, respectively.
Purpose of the Study:
- To investigate the impact of a newly identified Prnp allele, Prnp(c), on prion disease incubation time and neuropathology.
- To generate a congenic mouse line to isolate the effect of Prnp(c) from its original genetic background.
Main Methods:
- Sequencing of the prion gene open reading frame in inbred mouse lines.
- Generation of a congenic mouse line harboring Prnp(c) on a C57BL/6JOlaHsd background.
- Intracerebral inoculation with Chandler/RML scrapie prions and assessment of incubation time, PrP deposition, and spongiosis.
Main Results:
- The congenic mice with Prnp(c) exhibited a mean incubation time over 100 days longer than controls.
- No significant differences in PrP immunoreactivity deposition or spongiosis were observed between groups.
- The Prnp(c) allele was identified in the MAI/Pas mouse strain.
Conclusions:
- The novel Prnp(c) allele significantly modulates prion disease incubation time in mice.
- Prnp(c) does not appear to influence the neuropathological characteristics of prion disease.
- The established classification of mice into two groups based on Prnp genotype and incubation time requires revision.
