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Title: Functional analysis of Hectd2 : a prion disease modifier associated with incubation time
Author: Begum, R.
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2013
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Prion diseases in mice are characterised by prolonged, clinically silent incubation periods that are distinct in duration and reproducible. Incubation times are influenced by a number of factors with the major genetic determinant being variation within the prion protein gene, Prnp, however, different lines of inbred mice with identical Prnp genotypes show differences in incubation time indicative of a multi-genic effect. A heterogeneous stock of mice was used for fine mapping studies from which emerged several candidate genes including Hectd2, an E3 ubiquitin ligase. A human association study found that this genetic modifier is associated with an increased risk to vCJD and kuru. To characterise Hectd2, a yeast two hybrid screen was performed to search for novel interactors, yielding twenty binding partners. Selected candidates were verified by co-immunoprecipitation in mammalian cells. These included Sh3glb1, which has been linked to autophagy in a Parkinson’s disease model as well as Stambp, which encodes a deubiquitination protein in the CNS, and Stmn2, a gene previously associated with susceptibility to vCJD in a genome wide association study. Pacsin2 and Sept7, also emerged as Hectd2 interactors. These proteins operate in the cytoskeletal network, serving a regulatory role for maintaining neuronal integrity, a pathway not previously recognised in prion pathology. By application of a cell based model of prion propagation, the Scrapie Cell Assay, it has been possible to establish the effect of knocking down candidate genes on cell susceptibility thus providing a direct link with prion pathology. In addition, Hectd2 knockout and transgenic overexpressing mouse models were challenged with three strains of mouse adapted prions to search for an association with incubation time. In conclusion, this has been the first attempt at interactome mapping of a candidate gene associated with incubation time in mouse and susceptibility to human diseases. We have identified novel gene candidates that are implicated in prion pathology, thus providing an insight into the possible pathways that modulate prion disease.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available