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Identification of a novel putative PrP receptor.

Cipriani, F.; (2005) Identification of a novel putative PrP receptor. Doctoral thesis , University of London. Green open access

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Prion diseases, also known as Transmissible Spongiform Encephalopathies (TSEs), are fatal conditions which affect humans and animals. The hallmark of Transmissible Spongiform Encephalopathies is the accumulation in the brain of PrPSc, which is an abnormal isoform of the cellular protein PrPc. It has been proposed that PrPSc is able to impose its own conformation on PrP , but the molecular mechanism by which PrP is converted into PrPSc is unclear. PrPc and PrPSc share the same primary sequence but they are different in their biochemical properties. PrP is rich in alpha helices, detergent soluble and Protease K sensitive on the other hand, PrPSc is mainly composed of beta sheets, detergent insoluble and Protease K resistant. To better understand PrPSc generation, a genetic screen to identify proteins that preferentially interact with a misfolded version of PrP has been employed. This novel protein-protein interaction system takes place in the yeast cytoplasm where PrP has been reported to adopt a beta sheet-rich conformation characterised by increased Protease K resistance. Initial analysis revealed that one candidate molecule, PrP Interacting Protein 7 (PIP7), encoded a transmembrane protein present on the cell surface, suggesting a potential function as a novel PrP receptor. The interaction between PIP7 and PrP has been confirmed in vitro by GST pull down experiments and in vivo by co- immunoprecipitation studies. A panel of monoclonal antibodies directed against the C- terminus of PIP7, which contains the PrP binding region, has been generated. FACS analysis using these antibodies confirmed the presence of PIP7 on the cell surface of N2a cells, commonly used to study PrPSc propagation, and PIP7 immunohistochemistry has revealed an intense staining in all brain regions including the cortex, hippocampus and cerebellum. Overexpression of PrP in N2a cells resulted in an accumulation of PIP7 surface levels. Furthermore, PIP7 levels appear to be reduced in the brains of PrP knockout mice. The direct correlation between the levels of PIP7 and PrP suggests a potential role for PIP7 as a regulator in prion biology.

Type: Thesis (Doctoral)
Title: Identification of a novel putative PrP receptor.
Identifier: PQ ETD:591984
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > SoP Pharmaceutical and Bio Chemistry
URI: http://discovery.ucl.ac.uk/id/eprint/1444675
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