eprintid: 146077
rev_number: 58
eprint_status: archive
userid: 608
dir: disk0/00/14/60/77
datestamp: 2010-10-28 05:02:43
lastmod: 2021-10-04 01:07:11
status_changed: 2010-10-28 05:02:43
type: article
metadata_visibility: show
item_issues_count: 0
creators_name: Lloyd, SE
creators_name: Maytham, EG
creators_name: Pota, H
creators_name: Grizenkova, J
creators_name: Molou, E
creators_name: Uphill, J
creators_name: Hummerich, H
creators_name: Whitfield, J
creators_name: Alpers, MP
creators_name: Mead, S
creators_name: Collinge, J
title: HECTD2 Is Associated with Susceptibility to Mouse and Human Prion Disease
ispublished: pub
divisions: UCL
divisions: B02
divisions: C07
divisions: DF9
divisions: FA5
keywords: QUANTITATIVE TRAIT LOCI, CREUTZFELDT-JAKOB-DISEASE, UBIQUITIN-PROTEASOME SYSTEM, LONG INCUBATION PERIODS, COMPLEX TRAITS, OUTBRED MICE, KURU, PROTEIN, IDENTIFICATION, SCRAPIE
note: © 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.
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.
date: 2009-02-13
publisher: PUBLIC LIBRARY SCIENCE
official_url: http://dx.doi.org/10.1371/journal.pgen.1000383
vfaculties: VFBRS
oa_status: green
pmcid: PMC2633041
language: eng
primo: open
primo_central: open_green
article_type_text: Article
verified: verified_batch
elements_source: Web of Science
elements_id: 130022
doi: 10.1371/journal.pgen.1000383
language_elements: EN
lyricists_name: Collinge, John
lyricists_name: Hummerich, Holger
lyricists_name: Lloyd, Sarah
lyricists_name: Mead, Simon
lyricists_name: Whitfield, Jerome Thomas
lyricists_id: JCOLL20
lyricists_id: HHUMM25
lyricists_id: SLLOY55
lyricists_id: SMEAD68
lyricists_id: JTWHI49
full_text_status: public
publication: PLOS GENET
volume: 5
number: 2
article_number: e1000383
issn: 1553-7390
citation:        Lloyd, SE;    Maytham, EG;    Pota, H;    Grizenkova, J;    Molou, E;    Uphill, J;    Hummerich, H;                 ... Collinge, J; + view all <#>        Lloyd, SE;  Maytham, EG;  Pota, H;  Grizenkova, J;  Molou, E;  Uphill, J;  Hummerich, H;  Whitfield, J;  Alpers, MP;  Mead, S;  Collinge, J;   - view fewer <#>    (2009)    HECTD2 Is Associated with Susceptibility to Mouse and Human Prion Disease.                   PLOS GENET , 5  (2)    , Article e1000383.  10.1371/journal.pgen.1000383 <https://doi.org/10.1371/journal.pgen.1000383>.       Green open access   
 
document_url: https://discovery.ucl.ac.uk/id/eprint/146077/1/146077.pdf