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Title: Presenilin signalling in a basic biomedical model
Author: Ludtmann, Marthe Helene Regina
Awarding Body: Royal Holloway, University of London
Current Institution: Royal Holloway, University of London
Date of Award: 2012
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Familial Alzheimer's disease is often caused by mutated forms of one of two highly related presenilin proteins. In order to unravel the effects on signalling pathways caused by these aberrant proteins, a model is required in which all wild-type presenilin protein activity is deleted to enable the investigation of disease-related signal transduction. Deletion of both mammalian presenilin genes is highly problematic, as gene deletion causes lethality at an early embryonic stage. Therefore, this current study set out to develop a model system to aid the understanding of presenilin protein signalling. Dictyostelium discoideum is the simplest biomedical model possessing two presenilin homologues (PsenA and PsenB). Deletion of either D. discoideum presenilin gene did not cause an aberrant developmental morphology, however, deletion of both presenilin genes led to a severe developmental phenotype. This phenotype was rescued by reintroducing D. discoideum psenB, suggesting a compensatory mechanism of both D. discoideum presenilin proteins. Functionality of this model in the analysis of the human PS1 (hPS1) was shown through expression of hPS1 in the D. discoideum presenilin null background. hPS1 expression restored wild-type development, suggesting the human protein is functional in D. discoideum. A conserved function between human and D. discoideum proteins was established through a Notch cleavage assay. Analysis revealed that both D. discoideum presenilin proteins were able to cleave Notch, confirming a functional conservation. Calcium dysregulation has previously been linked to FAD and presenilin proteins. The work presented here revealed that calcium influx into the cytosol was significantly upregulated in D. discoideum presenilin mutant cells. This study is the first to describe a conserved function between human and D. discoideum presenilin proteins. This model provides therefore an excellent system to further investigate cellular roles of human presenilin in basic cell function and disease-related signalling.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Presenilin ; Dictyostelium discoideum ; Alzheimer's disease