hectd2 is associated with susceptibility to mouse and human prion diseasehectd2与老鼠和人类朊病毒疾病的易感性.pdfVIP

HECTD2 Is Associated with Susceptibility to Mouse and Human Prion Disease Sarah E. Lloyd1,2, Emma G. Maytham1,2, Hirva Pota1,2, Julia Grizenkova1,2, Eleni Molou1,2, James Uphill1,2, Holger Hummerich1,2, Jerome Whitfield1,2,3, Michael P. Alpers1,2,4, Simon Mead1,2, John Collinge1,2* 1 MRC Prion Unit, University College London Institute of Neurology, London, United Kingdom, 2 Department of Neurodegenerative Diseases, University College London Institute of Neurology, London, United Kingdom, 3 Papua New Guinea Institute of Medical Research, Goroka, Eastern Highlands Province, Papua New Guinea, 4 Centre for International Health, Curtin University, Perth, Australia 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