Our data show that HECTD2
is linked to prion disease incubation time in mouse and is associated with sporadic and variant CJD and kuru in humans and an increase in expression is associated with a susceptibility genotype and disease pathogenesis. In mouse, we cannot exclude the possibility of other nearby genes or intergenic regions also being implicated as our sequencing studies were not exhaustive. However, in human, the LD block, based on HapMap 
data, includes only HECTD2
and does not extend into the neighbouring genes suggesting that the association observed stems from HECTD2
and not any other gene in the area.
In mouse, the promoter, 3′UTR polymorphisms and the associated differential expression suggest a mechanism by which Hectd2 may influence the incubation time phenotype. Similarly, in the UK population a promoter polymorphism is also associated with a susceptibility phenotype and a resulting increase in expression level. This suggests that the mode of HECTD2 action in prion disease may be independent of host and prion strain. Due to lack of available material it has not been possible to replicate these experiments in our kuru samples, however, our haplotype study suggest that a different polymorphism is likely to be functional in the PNG population. This does not rule out the possibility that differential expression is also important in PNG, through an alternative polymorphism, although this may be difficult to determine. Our expression analysis in terminally sick mice suggest that HECTD2 is upregulated during the course of infection therefore we can speculate that a higher base line of expression reduces the time taken to reach a threshold level thereby reducing the incubation time.
The ubiquitin-proteosome system has been implicated in the pathogenesis of several neurodegenerative diseases which show an accumulation of an abnormally folded protein including prion disease, Parkinson's disease and Alzheimer's disease 
. By homology to other family members, HECTD2 is an E3 ubiquitin ligase suggesting that common pathways are involved in the neurodegenerative processes of these different diseases. Specifically, the mouse mahoganoid
coat-colour mutation is found in the gene Mahogunin
which is an E3 ubiquitin ligase 
. A null mutation of Mahogunin
causes an age-related progressive neurodegenerative phenotype characterised by spongiform degeneration, neuronal loss and astrocytosis. The phenotype resembles that of prion disease however there is no PrPSc
accumulation. Mutations in the E3 ubiquitin ligase parkin are associated with autosomal recessive juvenile parkinsonism and loss of ubiquitin-protein ligase activity in patients has been shown to be associated with protein accumulation 
. E3 ubiquitin ligases have also been implicated in the pathogenesis of polyglutamine diseases in particular it has been shown that mutations in the E6-AP ubiquitin ligase reduces the frequency of nuclear inclusions in mice expressing mutant ataxin-1 while accelerating the Purkinje cell pathology 
. Further, HECTD2
maps to a region of human chromosome 10q previously linked with Alzheimer's disease 
suggesting that HECTD2
may also be a susceptibility factor for Alzheimer's disease and other neurodegenerative disorders.
Group sizes for vCJD, kuru and elderly female survivors of mortuary feasts are of necessity small, however we believe that the combined weight of data from the mouse genetic studies, expression analyses and our association study of independent human prion diseases from different populations provide sufficient evidence to support a role for HECTD2 in prion disease. This supports a significant role for the ubiquitin-proteasome system in prion pathogenesis 
and will contribute to modelling and understanding genetic risk of developing prion disease following BSE and secondary human prion exposure.