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Updated: Jun 25, 2026
A Phenotyping Regimen for Genetically Modified Mice Used to Study Genes Implicated in Human Diseases of Aging
Published on: July 14, 2016
HECTD2 is associated with susceptibility to mouse and human prion disease
Sarah E Lloyd1, Emma G Maytham, Hirva Pota
1MRC Prion Unit, University College London Institute of Neurology, London, United Kingdom.
Abstract:
Prion diseases are fatal transmissible neurodegenerative disorders, which include Scrapie, Bovine Spongiform Encephalopathy (BSE), Creutzfeldt-Jakob Disease (CJD), and kuru. They are characterised by a prolonged clinically silent incubation period, variation in which is determined by many factors, including genetic background. We have used a heterogeneous stock of mice to identify Hectd2, an E3 ubiquitin ligase, as a quantitative trait gene for prion disease incubation time in mice. Further, we report an association between HECTD2 haplotypes and susceptibility to the acquired human prion diseases, vCJD and kuru. We report a genotype-associated differential expression of Hectd2 mRNA in mouse brains and human lymphocytes and a significant up-regulation of transcript in mice at the terminal stage of prion disease. Although the substrate of HECTD2 is unknown, these data highlight the importance of proteosome-directed protein degradation in neurodegeneration. This is the first demonstration of a mouse quantitative trait gene that also influences susceptibility to human prion diseases. Characterisation of such genes is key to understanding human risk and the molecular basis of incubation periods.
Insights
Researchers identified Hectd2 as a gene influencing prion disease incubation in mice. This gene also impacts human susceptibility to prion diseases like vCJD and kuru, offering insights into neurodegeneration.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Prion diseases are fatal, transmissible neurodegenerative disorders with long incubation periods influenced by genetics.
- Examples include Scrapie, Bovine Spongiform Encephalopathy (BSE), Creutzfeldt-Jakob Disease (CJD), and kuru.
- Understanding genetic factors is crucial for prion disease risk assessment and understanding incubation periods.
Purpose of the Study:
- To identify genes controlling prion disease incubation time in mice.
- To investigate the role of identified genes in human prion disease susceptibility.
- To explore the molecular mechanisms underlying prion disease pathogenesis.
Main Methods:
- Utilized a heterogeneous stock of mice for genetic analysis.
- Employed quantitative trait gene mapping to identify Hectd2.
- Analyzed HECTD2 haplotypes for association with human prion diseases (vCJD, kuru).
- Assessed Hectd2 mRNA expression in mouse brains and human lymphocytes.
Main Results:
- Identified Hectd2, an E3 ubiquitin ligase, as a quantitative trait gene for prion disease incubation in mice.
- Found an association between HECTD2 haplotypes and susceptibility to acquired human prion diseases (vCJD, kuru).
- Observed genotype-associated differential expression of Hectd2 mRNA and significant upregulation in terminal prion disease stages.
Conclusions:
- Hectd2 plays a role in regulating prion disease incubation periods in mice.
- HECTD2 influences susceptibility to human prion diseases, linking mouse models to human risk.
- These findings underscore the importance of proteasome-mediated protein degradation in neurodegeneration and prion disease.
- Characterizing such genes is vital for understanding human risk and the molecular basis of disease incubation periods.
