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HECTD2 Is Associated with Susceptibility to Mouse and Human Prion Disease

Lloyd, SE; Maytham, EG; Pota, H; Grizenkova, J; Molou, E; Uphill, J; Hummerich, H; ... Collinge, J; + view all (2009) HECTD2 Is Associated with Susceptibility to Mouse and Human Prion Disease. PLOS GENET , 5 (2) , Article e1000383. 10.1371/journal.pgen.1000383. Green open access

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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.

Type: Article
Title: HECTD2 Is Associated with Susceptibility to Mouse and Human Prion Disease
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pgen.1000383
Publisher version: http://dx.doi.org/10.1371/journal.pgen.1000383
Language: English
Additional information: © 2009 Lloyd et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was funded by the Medical Research Council, UK.
Keywords: QUANTITATIVE TRAIT LOCI, CREUTZFELDT-JAKOB-DISEASE, UBIQUITIN-PROTEASOME SYSTEM, LONG INCUBATION PERIODS, COMPLEX TRAITS, OUTBRED MICE, KURU, PROTEIN, IDENTIFICATION, SCRAPIE
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Institute of Prion Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Institute of Prion Diseases > MRC Prion Unit at UCL
URI: https://discovery.ucl.ac.uk/id/eprint/146077
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