Title: Genetic risk factors and other characteristics which contribute to pathogenesis in human prion disease, including vCJD
Funder: Department of Health (England)

Abstract: Background Creutzfeldt-Jakob disease (CJD) is the most common human prion disease. Most cases are sporadic (sCJD), however the BSE epidemic in the UK resulted in a new form, variant CJD (vCJD). Surveillance has identified 177 vCJD cases in the UK, with incidence peaking in 2000. The known spectrum of human prion diseases continues to broaden, as shown by the recent identification of variable protease sensitive prionopathy (VPSPr). There remain areas of uncertainty regarding susceptibility, pathogenic processes and the risks of secondary transmission. The responsible agent or prion is a conformationally altered form (PrPSc) of the cellular prion protein (PrPC) and disease susceptibility and phenotype is thought to result from interplay between host genetics and agent strain. Aims Genetic susceptibility: vCJD and sCJD differ fundamentally in terms of aetiology. Susceptibility to both diseases is influenced by the common methionine (M) / valine (V) polymorphism at codon 129 of PRNP, but it also seems likely that other loci are involved in susceptibility to vCJD and/or sCJD. This proposal seeks to identify new candidate loci. Seeding ability: The spectrum of PrPSc isoforms is only partly characterised. We propose characterising the full range of biochemical forms present in VPSPr as compared to sCJD and to determine whether PrPSc aggregate size affect its ability to seed further conversion. Seeding ability can be exploited in the form of a CSF test for sCJD (termed RT-QuIC), which offers the possibility of earlier clinical diagnosis. However, the RT-QuIC test in its present form is not optimised for vCJD CSF specimens but may be modified to do so. Peripheral and central replication: The appendix survey suggests a far higher incidence of asymptomatic vCJD than the numbers of clinical cases suggest. The VV genotype appears to be over-represented in the positive appendix group. We have recently shown that human tonsil derived cells (of the VV genotype) can degrade PrPSc efficiently. We now wish to directly compare these VV cells with their MV and MM counterparts to see whether genotype might be a factor in progression from peripheral infection to neuroinvasion. Human neurones and glia can now be derived from human stem cells. These cells may offer advantages over other neuronal cellular models for human prion diseases. Plan First, this proposal seeks to identify candidate sCJD and vCJD susceptibility loci using whole genome sequencing on a limited number of cases. Secondly, we propose characterising the full range of biochemical forms present in VPSPr as compared to sCJD and to determine whether PrPSc aggregate size affect its ability seed further conversion. Additionally, we will test a series of different recombinant PrP sequences and other methodological modifications to determine whether the CSF QuIC assay can be adapted to test for vCJD. Lastly we will compare the balance of PrPSc replication / degradation in human tonsil derived cell lines of all three codon 129 genotypes and test whether human stem cell derived neurones and glia have the minimal requirements necessary to support vCJD prion replication using the protein misfolding cyclic amplification assay. Team The research will be conducted by an integrated team of scientists working at the NCJdrSU. Impact The outcomes will help to resolve areas of current uncertainty for policy makers by producing data relevant to susceptibility, prevalence, progression and risks associated with vCJD and other human prion diseases.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL