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HECTD2 is associated with susceptibility to mouse and human prion disease.

HECTD2 is associated with susceptibility to mouse and human prion disease.

Authors :
Sarah E Lloyd
Emma G Maytham
Hirva Pota
Julia Grizenkova
Eleni Molou
James Uphill
Holger Hummerich
Jerome Whitfield
Michael P Alpers
Simon Mead
John Collinge
Source :
PLoS Genetics, Vol 5, Iss 2, p e1000383 (2009)
Publication Year :
2009
Publisher :
Public Library of Science (PLoS), 2009.

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.

Subjects

Subjects :
Genetics
QH426-470

Details

Language :
English
ISSN :
15537390 and 15537404
Volume :
5
Issue :
2
Database :
Directory of Open Access Journals
Journal :
PLoS Genetics
Publication Type :
Academic Journal
Accession number :
edsdoj.236d7807b243039970fe21131ee691
Document Type :
article
Full Text :
https://doi.org/10.1371/journal.pgen.1000383