Use this URL to cite or link to this record in EThOS:
Title: The cytopathology of familial encephalopathy with neuroserpin inclusion bodies (FENIB)
Author: Davies, Mark James
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2007
Availability of Full Text:
Full text unavailable from EThOS.
Please contact the current institution’s library for further details.
Neuroserpin is a 55 kDa glycoprotein that is secreted from axons of the central and peripheral nervous system. Point mutations within the neuroserpin gene underlie the novel inclusion body dementia Familial Encephalopathy with the Neuroserpin Inclusion Bodies (FENIB).  These point mutations destabilise the molecule resulting in the formation of intracellular polymers by sequential insertion of the reactive centre loop of one molecule into β-sheet A of another. Here I postulate that endoplasmic reticulum (ER) inclusions of mutant serpins contribute to the molecular pathogenesis by directing a novel ER stress response. To assess this hypothesis I generated conditional PC-12 Tet-on cell lines expressing wild type neuroserpin, the Ser52Arg and Gly392Glu mutants that underlie FENIB and a novel-misfolding mutant (DeltaNS) predicted to stimulate the unfolded protein response (UPR). The mutants that cause FENIB accumulate within the ER as polymers that I can demonstrate by Western blot analysis and fluorescence confocal microscopy with novel monoclonal antibodies that detect the polymeric conformer of neuroserpin. Despite accumulating, the mutant neuroserpin does not elicit a UPR. However I demonstrate that the ER accumulation of mutant neuroserpin elicits an ER stress response resulting in activation of NF-κB, and this activation is calcium dependent.  Taken together, I have used the disease-related neuroserpin inclusions to define and characterise a novel ER derived signalling cascade involved in sensing protein accumulation within the ER.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available