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Sod1 deficiency reduces incubation time in mouse models of prion disease
Shaheen Akhtar1, Julia Grizenkova, Adam Wenborn
1Medical Research Council Prion Unit and Department of Neurodegenerative Disease, University College London Institute of Neurology, London, United Kingdom.
Abstract:
Prion infections, causing neurodegenerative conditions such as Creutzfeldt-Jakob disease and kuru in humans, scrapie in sheep and BSE in cattle are characterised by prolonged and variable incubation periods that are faithfully reproduced in mouse models. Incubation time is partly determined by genetic factors including polymorphisms in the prion protein gene. Quantitative trait loci studies in mice and human genome-wide association studies have confirmed that multiple genes are involved. Candidate gene approaches have also been used and identified App, Il1-r1 and Sod1 as affecting incubation times. In this study we looked for an association between App, Il1-r1 and Sod1 representative SNPs and prion disease incubation time in the Northport heterogeneous stock of mice inoculated with the Chandler/RML prion strain. No association was seen with App, however, significant associations were seen with Il1-r1 (P = 0.02) and Sod1 (P<0.0001) suggesting that polymorphisms at these loci contribute to the natural variation observed in incubation time. Furthermore, following challenge with Chandler/RML, ME7 and MRC2 prion strains, Sod1 deficient mice showed highly significant reductions in incubation time of 20, 13 and 24%, respectively. No differences were detected in Sod1 expression or activity. Our data confirm the protective role of endogenous Sod1 in prion disease.
Insights
Genetic variations in Il1-r1 and Sod1 influence prion disease incubation periods in mice. Sod1 deficiency significantly shortens incubation times, confirming its protective role against prion infections.
Area of Science:
- Neuroscience
- Genetics
- Infectious Diseases
Background:
- Prion diseases, including Creutzfeldt-Jakob disease and BSE, have long and variable incubation periods.
- Genetic factors, such as polymorphisms in the prion protein gene, influence these incubation times.
- Previous studies identified App, Il1-r1, and Sod1 as candidate genes affecting incubation periods.
Purpose of the Study:
- To investigate the association between specific SNPs in App, Il1-r1, and Sod1 and prion disease incubation times.
- To determine the effect of Sod1 deficiency on incubation times across different prion strains.
Main Methods:
- Genotyping of representative SNPs in App, Il1-r1, and Sod1 in mice.
- Inoculation of mice with the Chandler/RML prion strain to measure incubation times.
- Inoculation of Sod1-deficient mice with Chandler/RML, ME7, and MRC2 prion strains.
Main Results:
- Significant associations were found between polymorphisms in Il1-r1 (P = 0.02) and Sod1 (P<0.0001) and prion disease incubation time.
- Sod1-deficient mice exhibited significantly reduced incubation times (20-24%) across three prion strains.
- No differences in Sod1 expression or activity were detected between groups.
Conclusions:
- Polymorphisms in Il1-r1 and Sod1 contribute to the natural variation in prion disease incubation times.
- Endogenous Sod1 plays a protective role in prion disease, as evidenced by reduced incubation times in Sod1-deficient mice.
