HECTD2 is associated with susceptibility to mouse and human prion disease
| Autor: | Holger Hummerich, Hirva Pota, Sarah E. Lloyd, Jerome Whitfield, John Collinge, Simon Mead, Julia Grizenkova, Emma G. Maytham, Eleni Molou, Michael P. Alpers, James Uphill |
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| Rok vydání: | 2008 |
| Předmět: |
Male
Cancer Research animal diseases Gene Expression Scrapie Prion Diseases Rodent Diseases Mice Lymphocytes Genetics (clinical) Cells Cultured Genetics and Genomics/Genetics of Disease Genetics Slow virus biology Neurodegeneration Genetics and Genomics/Gene Expression Middle Aged Ubiquitin ligase Neurological Disorders/Prion Diseases Kuru Female Genetics and Genomics/Gene Discovery Research Article Adult lcsh:QH426-470 Adolescent Bovine spongiform encephalopathy Ubiquitin-Protein Ligases Quantitative Trait Loci Protein degradation Genetics and Genomics/Complex Traits Polymorphism Single Nucleotide White People Incubation period Young Adult medicine Animals Humans Genetic Predisposition to Disease Molecular Biology Ecology Evolution Behavior and Systematics Aged medicine.disease Virology nervous system diseases lcsh:Genetics Genetics and Genomics/Disease Models biology.protein |
| Zdroj: | PLoS Genetics PLoS Genetics, Vol 5, Iss 2, p e1000383 (2009) |
| ISSN: | 1553-7404 |
| Popis: | 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. Author Summary Prion diseases are fatal transmissible neurodegenerative diseases of animals and humans for which there is no treatment. They include Bovine Spongiform Encephalopathy (BSE), and its human equivalent, variant Creutzfeldt-Jakob Disease (vCJD). Prion diseases are characterised by a long, silent incubation period before the disease emerges, and this time interval varies greatly between individuals. Differences in our genetic makeup are a key factor in this variability. We already know that natural variation within one key gene, the prion protein gene, has a major influence on incubation time, but it is now clear that a number of other genes are also important. Using a mouse model, we have identified one of these genes, Hectd2, which is thought to be involved in the process that removes unwanted proteins from the cell. We also show that HECTD2 is associated with an increased risk of two human prion diseases—vCJD in the United Kingdom and kuru in Papua New Guinea. These data will give us a better understanding of the fundamental processes involved in these diseases and go some way to explaining why some individuals exposed to BSE have developed vCJD and others have not. |
| Databáze: | OpenAIRE |
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