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Similar target, different effects: late-onset ataxia and spatial learning in prion protein-deficient mouse lines
Abstract:
Several lines of mice with targeted deletion of the prion protein gene (Prnp) have been produced, some of them appearing phenotypically normal, others developing late-onset ataxia. This has been tentatively attributed to the size of the targeted deletion in the Prnp gene. but a masking role of genetic background could not be excluded. Thus, we have crossed an ataxic mutant line with large deletion of Prnp (Ngsk Prnp0/0) with a knockout line showing only partial deletion of Prnp and no neurological deficits (Zrchl Prnp0/0). A F2 generation was then studied for up to 70 weeks for co-segregation of lesion size and behavioral phenotype, including cognitive and neurological anomalies. These mice were later crossed with a recently generated PrP-deficient line also having a large deletion and late-onset ataxia (Zrch2 Prnp0/0). They underwent similar testing for up to 90 weeks. The ataxic phenotype always co-segregates with large homozygous deletions involving either the Ngsk or the Zrch2 allele, independent of genetic background or sex. Compound heterozygous Zrchl/Ngsk mice or Zrch1/Zrch2 mice showed intermediate neurological phenotypes, suggesting a gene-dosage effect of large deletions. At 12 weeks of age, large deletions were also associated with minor non-cognitive impairments in water maze learning, and hyperactivity in open field and elevated zero maze. These impairments were not predictive for the development of ataxia. Thus, the neurological deficits are closely associated with large deletions, which entail an upregulation of the recently discovered prion Doppel protein (Dpl), while genetic background factors seem to be responsible for shifting the onset of neurological symptoms.
Insights
Large deletions in the prion protein gene (Prnp) cause ataxia in mice, linked to Doppel protein (Dpl) upregulation. Genetic background influences symptom onset but not the ataxia itself.
Area of Science:
- Neuroscience
- Genetics
- Prion Biology
Background:
- Targeted deletion of the prion protein gene (Prnp) in mice has yielded varied phenotypes, including ataxia, with the cause debated.
- The size of the deletion and genetic background have been proposed as factors influencing Prnp deletion phenotypes.
Purpose of the Study:
- To investigate the co-segregation of Prnp deletion size and neurological phenotypes in mice.
- To determine the influence of genetic background and sex on Prnp deletion-associated ataxia.
- To explore the role of gene dosage in Prnp deletion phenotypes.
Main Methods:
- Crossed ataxic Ngsk Prnp0/0 mice with non-ataxic Zrchl Prnp0/0 mice, analyzing the F2 generation for phenotype-lesion size co-segregation.
- Further crossed F2 mice with Zrch2 Prnp0/0 mice, conducting behavioral testing up to 90 weeks.
- Assessed cognitive and neurological anomalies, including water maze learning and open field tests.
Main Results:
- Ataxic phenotype consistently co-segregated with large homozygous Prnp deletions (Ngsk or Zrch2 alleles), irrespective of genetic background or sex.
- Compound heterozygous mice (Zrchl/Ngsk or Zrch1/Zrch2) exhibited intermediate neurological phenotypes, indicating a gene-dosage effect.
- Large deletions were associated with minor learning impairments and hyperactivity at 12 weeks, but these did not predict ataxia development.
Conclusions:
- Neurological deficits in Prnp-deleted mice are strongly linked to large deletions, which upregulate the Doppel protein (Dpl).
- Genetic background factors modulate the onset of neurological symptoms rather than causing the ataxia itself.
- The study clarifies the relationship between Prnp deletion size, Dpl upregulation, and ataxia, highlighting gene dosage effects.
